TW202206422A - Compounds and methods for cd73 modulation and indications therefor - Google Patents

Abstract

Disclosed are compounds of Formula I: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein R1, R2, R3, A, E, L, and G are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.

Description

用於CD73調節之化合物及方法及其適應症Compounds and methods for CD73 modulation and their indications

本發明係關於適用於哺乳動物中之療法，且尤其適用於調節與CD73之過度表現相關之各種疾病的CD73的有機化合物。The present invention relates to organic compounds suitable for use in therapy in mammals, and in particular for modulating CD73 in various diseases associated with overexpression of CD73.

已發現催化AMP分解為腺苷之酶CD73在多種類型之癌症中過度表現。CD73參與細胞外腺苷之生成，其調節T細胞之腫瘤誘導的免疫抑制機制，從而使腫瘤衍生之CD73充當胞外酶以產生細胞外腺苷，該細胞外腺苷藉由限制經由腺苷受體（AR）信號傳導之抗腫瘤T細胞免疫來促進腫瘤生長。更特定言之，CD73（高度保守的胞外核苷酸酶）為表現於質膜之外小葉上之二聚酶。其催化5'核苷酸之子集的去磷酸化，其中5'-腺苷單磷酸酯（AMP）為主要底物。腺苷係藉由CD73催化之AMP在腫瘤微環境中以高位準水解產生。其結合至免疫細胞上之A2a及A2b受體且抑制針對腫瘤細胞之免疫監視。阻斷AMP之CD73水解為抑制抗腫瘤免疫之潛在治療方法。鼠類腫瘤模型中靶向CD73之小分子抑制劑的結果表明靶向CD73療法為有效控制腫瘤生長之重要替代及現實方法。特定言之，其藉由增強適應性免疫反應機制而幫助基於T細胞之療法，其可增加腫瘤浸潤T淋巴細胞之功能且隨後提高癌症患者之存活期。The enzyme CD73, which catalyzes the breakdown of AMP to adenosine, has been found to be overexpressed in various types of cancer. CD73 is involved in the production of extracellular adenosine, which modulates tumor-induced immunosuppressive mechanisms of T cells, allowing tumor-derived CD73 to act as an extracellular enzyme to produce extracellular adenosine, which is mediated by restriction through adenosine receptors. Antitumor T-cell immunity through body (AR) signaling to promote tumor growth. More specifically, CD73 (a highly conserved extracellular nucleotidase) is a dimerase expressed on leaflets outside the plasma membrane. It catalyzes the dephosphorylation of a subset of 5' nucleotides with 5'-adenosine monophosphate (AMP) as the primary substrate. Adenosine is produced by CD73-catalyzed hydrolysis of AMP at high levels in the tumor microenvironment. It binds to A2a and A2b receptors on immune cells and inhibits immune surveillance against tumor cells. Blocking CD73 hydrolysis of AMPs is a potential therapeutic approach to suppress antitumor immunity. The results of small molecule inhibitors targeting CD73 in murine tumor models suggest that targeting CD73 therapy is an important alternative and realistic approach to effectively control tumor growth. In particular, it aids T cell-based therapy by enhancing adaptive immune response mechanisms, which can increase the function of tumor-infiltrating T lymphocytes and subsequently improve the survival of cancer patients.

已報導，基於臨床試驗資料，CD73表現與人類TNBC中之不良預後及減少之抗腫瘤免疫性相關且靶向CD73可為在此BC亞型中再程式化腫瘤微環境之有前景的策略。（參見Bruissert等人，《CD73在三陰性乳癌中之臨床意義：III期臨床試驗之多重分析（Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial）》, 《腫瘤學年鑒 （Ann Oncol. ）》2018年4月1日，29（4）：1056-1062。）Based on clinical trial data, CD73 expression has been reported to be associated with poor prognosis and reduced anti-tumor immunity in human TNBC and targeting CD73 may be a promising strategy for reprogramming the tumor microenvironment in this BC subtype. (See Bruissert et al, "Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial", Oncology Ann Oncol. 2018 Apr 1, 29(4): 1056-1062.)

亦已報導CD73為免疫療法之標靶，且具有CD73抑制劑之臨床研究可證明有益於肺癌患者。（參見Hui等人，《評估肺癌中之CD73（Evaluation of CD73 in lung cancer）》, 《臨床腫瘤學雜誌 （Journal of Clinical Oncology ）》201735：15。）CD73 has also been reported as a target for immunotherapy, and clinical studies with CD73 inhibitors may prove beneficial for lung cancer patients. (See Hui et al., Evaluation of CD73 in lung cancer, Journal of Clinical Oncology 201735 :15.)

亦報導，越來越多的證據證明CD73係癌症發展中之關鍵調節分子，更具體而言，CD73在許多類型之癌細胞系及患者之活檢體（包括乳癌、大腸直腸癌、卵巢癌、胃癌及膽囊癌）中過度表現，且亦與癌症患者之臨床特徵或預後相關。此外，對腫瘤攜帶小鼠模型之積極作用表明抗CD73療法已成為治療此類癌症患者之有前景的方法。（參見Zhao-wei Gao等人，《CD73在癌症中之作用（The Roles of CD73 in Cancer）》, 《國際生物醫學研究 （BioMed Research International ）》，2014年卷）。It is also reported that there is increasing evidence that CD73 is a key regulatory molecule in cancer development, and more specifically, CD73 is expressed in many types of cancer cell lines and patient biopsies (including breast cancer, colorectal cancer, ovarian cancer, gastric cancer, etc.). and gallbladder cancer) and are also associated with clinical features or prognosis of cancer patients. Furthermore, the positive effect on tumor-bearing mouse models suggests that anti-CD73 therapy has become a promising approach for the treatment of patients with this type of cancer. (See Zhao-wei Gao et al., The Roles of CD73 in Cancer, BioMed Research International , vol. 2014).

已進一步證明，宿主CD73在神經膠質母細胞瘤發病機制之多個領域中起顯著作用，包括促進神經膠質母細胞瘤生長、其血管生成及其侵襲性。更具體而言，研究表明與假相比，GB上之A2B腺苷受體（AR）表現增加了20倍，且其抑制提高了神經膠質母細胞瘤對替莫唑胺之化學敏感性。此等發現強有力地指示，CD73及A2B AR之阻斷或抑制係未來神經膠質母細胞瘤療法之主要標靶。（參見Yan.A等人，《CD73經由A2B腺苷受體信號傳導促進神經膠質母細胞瘤之發病及增強其化學抗性（CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A2B Adenosine Receptor Signaling）》, 《神經科學 （J Neurosci .）》2019年5月29日；39（22）：4387-4402）。It has further been demonstrated that host CD73 plays a significant role in multiple areas of glioblastoma pathogenesis, including promoting glioblastoma growth, its angiogenesis, and its aggressiveness. More specifically, studies have shown a 20-fold increase in A2B adenosine receptor (AR) expression on GB compared to sham, and its inhibition increases the chemosensitivity of glioblastoma to temozolomide. These findings strongly suggest that blockade or inhibition of CD73 and A2B AR is a major target for future glioblastoma therapy. (See Yan. A et al., CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A2B Adenosine Receptor Signaling," Neuroscience ( J Neurosci . 2019 May 29;39(22):4387-4402).

研究已發現，CD73活性在神經膠質瘤細胞系中之增殖過程期間增加，表明此酶在腦瘤發展期間具有重要作用。綜合而言，此等結果表明神經膠質瘤細胞增殖中之胞外-50-NT/CD73之重要作用。（參見Luci Bavaresco等人，《胞外-5'-核苷酸酶/CD73在神經膠質瘤細胞系增殖中之作用（The role of ecto-5'-nucleotidase/CD73 in glioma cell line proliferation）》, 《分子與細胞生物化學 （Mol Cell Biochem ）》（2008）319：61-68）。Studies have found that CD73 activity is increased during the proliferative process in glioma cell lines, suggesting that this enzyme has an important role during brain tumor development. Taken together, these results suggest an important role for extracellular-50-NT/CD73 in glioma cell proliferation. (See Luci Bavaresco et al., "The role of ecto-5'-nucleotidase/CD73 in glioma cell line proliferation", Mol Cell Biochem (2008) 319:61-68).

進一步發現CD73表現較高之胃癌患者中總存活率較低，且CD73表現經證實為胃癌患者之獨立預測因子。（參見Lu XX等人，《胃癌中之CD73及低氧誘導型因子-1α之表現及臨床意義（Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma）》, 《世界胃腸病學雜誌 （World J Gastroenterol. ）》2013年3月28日；19（12）：1912-8）。It was further found that the overall survival rate was lower in gastric cancer patients with higher CD73 expression, and CD73 expression was confirmed to be an independent predictor of gastric cancer patients. (See Lu XX et al, Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma, World Gastroenterology Journal ( World J Gastroenterol. 2013 Mar 28;19(12):1912-8).

其他研究發現CD73表現某些病況增加，諸如黑色素瘤細胞系之高度侵襲性表型、增殖慢性淋巴球性白血病細胞、乳頭狀癌（甲狀腺癌之最常見形式）、胰管腺癌及大腸直腸癌基質。已發現，在神經膠質瘤細胞系、轉移***癌之淋巴結及人類腫瘤膀胱細胞系中，CD73 mRNA及活性增加。（參見Luca Antonioli等人，《癌症免疫療法中之抗CD73：喚醒新的機會（Anti-CD73 in cancer immunotherapy: awakening new opportunities）》, 《癌症趨勢 （Trends Cancer. ）》2016年2月1日；2（2）：95-, 109）。Other studies have found that CD73 is increased in certain conditions, such as a highly aggressive phenotype of melanoma cell lines, proliferating chronic lymphocytic leukemia cells, papillary carcinoma (the most common form of thyroid cancer), pancreatic duct adenocarcinoma, and colorectal cancer matrix. Increased CD73 mRNA and activity have been found in glioma cell lines, lymph node metastases from prostate cancer, and human tumor bladder cell lines. (See Luca Antonioli et al., Anti-CD73 in cancer immunotherapy: awakening new opportunities, Trends Cancer. 2016, Feb. 1; 2(2):95-, 109).

亦報導，抑制CD73以防止其免疫抑制作用可為有前景的治療標靶，因為其可增強白血病之控制。（參見Paolo Bernasconi等人，《靶向白血病幹細胞-小生境動力學：AML治療之新挑戰（Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment）》, 《腫瘤學雜誌 （Journal of Oncology ）》，2019年卷）。It has also been reported that inhibition of CD73 to prevent its immunosuppressive effects may be a promising therapeutic target as it may enhance leukemia control. (See Paolo Bernasconi et al., "Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment", Journal of Oncology , Vol. 2019).

其他研究發現與不良患者預後無關臨床病理學因素相關之胰臟癌細胞之高CD73表現，且此表明CD73可為胰管腺癌中之相關免疫治療標靶及有前景的免疫預後生物標記。（參見N. Messaoudi等人，《CD73作為胰臟腺癌之新穎免疫標靶及生物標記（CD73 as a novel immune target and biomarker in pancreatic adenocarcinoma）》,HPB 2018，20（S1），S5eS35）。Other studies have found high CD73 expression in pancreatic cancer cells unrelated to clinicopathological factors associated with poor patient prognosis, and this suggests that CD73 may be a relevant immunotherapy target and a promising immunoprognostic biomarker in pancreatic ductal adenocarcinoma. (See N. Messaoudi et al., "CD73 as a novel immune target and biomarker in pancreatic adenocarcinoma", HPB 2018, 20(S1), S5eS35).

亦已報導，相比於非轉移***癌中之表現，CD73在轉移***癌之淋巴結中之表現較高，表明CD73可為***癌轉移分子療法之相關特異性標靶。（參見Yang Q等人，《***癌中之CD73之過度表現與淋巴結轉移相關（Overexpression of CD73 in prostate cancer is associated with lymph node metastasis）》, 《病理學與腫瘤學研究 （Pathol Oncol Res. ）》2013年10月；19（4）：811-4）。It has also been reported that CD73 is highly expressed in lymph nodes of metastatic prostate cancer compared to non-metastatic prostate cancer, suggesting that CD73 may be a relevant specific target for metastatic molecular therapy in prostate cancer. (See Yang Q et al., "Overexpression of CD73 in prostate cancer is associated with lymph node metastasis", Pathol Oncol Res. 2013 Oct;19(4):811-4).

其他研究已報導限制CD73衍生之腺苷基本上抑制微神經膠質介導之神經發炎且改善帕金森氏病（Parkinson's disease）模型中多巴胺激導性神經元之活力及運動行為。作者得出結論，靶向諸如CD73之核苷酸代謝路徑以限制帕金氏病中之腺苷產生及神經發炎可為有前景的治療策略。（參見Fan Meng等人，《CD73衍生之腺苷藉由調節多巴胺信號傳導來控制發炎及神經退化（CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signaling）》, 《大腦 （Brain ）》，第142卷，第3期，2019年3月，第700-718頁）。Other studies have reported that restriction of CD73-derived adenosine substantially inhibits microglia-mediated neuroinflammation and improves dopamine-stimulated neuronal activity and motor behavior in a Parkinson's disease model. The authors conclude that targeting nucleotide metabolic pathways such as CD73 to limit adenosine production and neuroinflammation in Parkin's disease may be a promising therapeutic strategy. (See Fan Meng et al., "CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signaling", Brain , p . 142 Volume, No. 3, March 2019, pp. 700-718).

肝纖維化發展為對慢性炎症及持續肝臟損傷之反應。此病理過程係藉由肌纖維母細胞之活化及蓄積驅動。由於肌纖維母細胞分化，所以在肝星狀細胞、門脈成纖維細胞及纖維隔膜中上調CD73。已報導CD73缺陷小鼠對肝纖維化之發展具有抗性，表明其在纖維發生中之作用及腺苷產生。CD73可適用於預防肝纖維化。Liver fibrosis develops in response to chronic inflammation and persistent liver damage. This pathological process is driven by the activation and accumulation of myofibroblasts. CD73 is upregulated in hepatic stellate cells, portal fibroblasts and fibrous septa due to myofibroblast differentiation. CD73-deficient mice have been reported to be resistant to the development of liver fibrosis, suggesting a role in fibrogenesis and adenosine production. CD73 may be suitable for preventing liver fibrosis.

其他研究已報導CD73為調節早期阿茲海默氏病之新穎標靶，其中早期阿茲海默氏病之β-類澱粉蛋白模型中之突觸及記憶功能障礙取決於由CD73產生之ATP衍生之細胞外腺苷之形成增加。（參見Gonçalves等人，《早期阿茲海默氏病之β-類澱粉蛋白模型中之突觸及記憶功能障礙取決於ATP衍生之細胞外腺苷之形成增加（Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine）》, 《神經系統疾病 （Neurobiol Dis. ）》2019年12月；132：104570）。Other studies have reported CD73 as a novel target in the regulation of early Alzheimer's disease, where synaptic and memory dysfunction in the beta-amyloid model of early Alzheimer's disease depend on ATP-derived ATP generation from CD73 The formation of extracellular adenosine is increased. (See Gonçalves et al., "Synaptic and memory dysfunction in a beta-amyloid model of early Alzheimer's disease depends on increased ATP-derived extracellular adenosine formation. amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine), Neurobiol Dis. 2019 Dec;132:104570).

因此，可以抑制CD73之化合物代表能夠調節免疫反應及腫瘤生長之新穎類別之潛在治療劑。由於不存在當前批准用於治療或預防人類中之疾病之CD73抑制劑，因此仍需要新的能夠調節CD73之化合物。Thus, compounds that can inhibit CD73 represent a novel class of potential therapeutic agents capable of modulating immune responses and tumor growth. Since there are no CD73 inhibitors currently approved for the treatment or prevention of disease in humans, there remains a need for new compounds capable of modulating CD73.

本發明之一個實施例係關於新穎化合物，如本文中之任一實施例中所描述，或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中此等新穎化合物可以調節CD73。One embodiment of the present invention pertains to novel compounds, as described in any of the Examples herein, or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs thereof compounds, wherein these novel compounds can modulate CD73.

本發明之另一實施例係關於式I化合物：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中R¹ 、R² 、R³ 、A、E、L及G如本發明中之實施例中之任一者（包括其子實施例中之任一者）中所描述。Another embodiment of the present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein R ¹ , R ² , R ³ , A, E, L and G are as in the present invention as described in any of the embodiments (including any of its sub-embodiments).

在本發明中，在本文中進一步描述式I之其他實施例及子實施例。In this disclosure, other embodiments and sub-embodiments of Formula I are further described herein.

本發明之另一實施例係關於一種醫藥組合物，其包含根據式I之化合物或在本發明中，在本文中所描述之式I之任何實施例及子實施例，或此等化合物中之任一者之醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，及醫藥學上可接受之載劑或賦形劑。Another embodiment of the present invention pertains to a pharmaceutical composition comprising a compound according to formula I or, in the present invention, any embodiment and sub-embodiment of formula I described herein, or any of these compounds A pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog of any one, and a pharmaceutically acceptable carrier or excipient.

本發明之另一實施例係關於一種醫藥組合物，其包含根據式I之化合物或在本發明中，在本文中所描述之式I之任何實施例或此等化合物中之任一者之醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，及另一種治療劑。Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound according to formula I or, in the present invention, any embodiment of formula I described herein or a medicament of any of these compounds A pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog, and another therapeutic agent.

本發明之另一實施例係關於一種用於治療患有由CD73介導之疾病或病況之個體之方法，該方法包含向個體投與有效量之根據式I之化合物或本發明中所描述之式I之任何實施例或此等化合物中之任一者之醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，或如本發明中所描述之化合物中之任一者之醫藥組合物，其中疾病或病況異常地或以其他方式表現CD73或前述中之任一者之活化突變或易位。Another embodiment of the present invention pertains to a method for treating an individual having a disease or condition mediated by CD73, the method comprising administering to the individual an effective amount of a compound according to Formula I or as described in the present invention Any embodiment of Formula I or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog of any of these compounds, or as described in the present invention The pharmaceutical composition of any of the compounds of , wherein the disease or condition abnormally or otherwise expresses an activating mutation or translocation of CD73 or any of the foregoing.

本發明之實施方式中進一步描述其他實施例。Other embodiments are further described in the Embodiments of the Invention.

本申請案要求根據2020年4月23日提交的美國臨時申請63/014,523之35 U.S.C.§119（e）之權益，其特此以全文引用之方式併入。I. 定義This application claims the benefit of US Provisional Application 63/014,523 at 35 USC §119(e), filed April 23, 2020, which is hereby incorporated by reference in its entirety. I. Definitions

如本文所使用，除非另外明確指示，否則以下定義應適用：As used herein, unless expressly indicated otherwise, the following definitions shall apply:

在本文中應注意，如本文中及隨附權利要求書中所使用，除非上下文另外明確指示，否則單數形式「一」及「所述」包括複數個參考物。It should be noted herein that, as used herein and in the appended claims, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise.

除非另外指示連接點，否則本發明之式I之變數之定義中所列舉之化學部分及其所有實施例應自左至右閱讀，其中右側直接連接至如所定義之母體結構。然而，若在化學部分（例如，-烷氧基-C₁ -C₆ 烷基）之左側展示連接點（例如破折號「-」），則此化學部分之左側直接連接至如所定義之母體部分。Unless a point of attachment is indicated otherwise, chemical moieties recited in the definitions of the variables of formula I of the present invention and all examples thereof should be read from left to right, with the right side directly connected to the parent structure as defined. However, if a point of attachment (eg, a dash "-") is shown to the left of a chemical moiety (eg, -alkoxy-Ci _{- C6} alkyl), then the left side of this chemical moiety is directly attached to the parent moiety as defined .

假設在出於構築化合物之目的而考慮本文中所描述之化合物之一般描述時，此類構築引起產生穩定結構。亦即，一般熟習此項技術者之一將認識到，在理論上，一些構築體將通常不被視為穩定化合物（亦即，空間上切實可行的及/或在合成上可行的）。It is assumed that when the general description of the compounds described herein is considered for the purpose of building the compounds, such building results in the creation of stable structures. That is, one of ordinary skill in the art will recognize that, in theory, some constructs will generally not be considered stable compounds (ie, sterically feasible and/or synthetically feasible).

除非另外說明，否則單獨或作為另一取代基之一部分的「烷基」意謂具有指定碳原子數目之直鏈或分支鏈烴（亦即，C_1- C₆ 意謂一至六個碳）。代表性烷基包括具有1、2、3、4、5、6、7、8、9、10、11或12個碳原子之直鏈及分支鏈烷基。其他代表性烷基包括具有1、2、3、4、5、6、7或8個碳原子之直鏈及分支鏈烷基。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、三級丁基、異丁基、二級丁基、正戊基、正己基、正庚基、正辛基及其類似者。對於本文中之定義中之每一者（例如烷基、烷氧基、芳基烷基、環烷基烷基、雜環烷基烷基、雜芳基烷基等），在不包括前綴來指示烷基部分中之碳原子數目時，烷基部分或其部分具有12個或更少的主鏈碳原子，或8個或更少的主鏈碳原子，或6個或更少的主鏈碳原子。舉例而言，C₁ -C₆ 烷基係指具有1、2、3、4、5或6個碳原子之直鏈或分支鏈烴，包括但不限於-CH₃ 、C₂ 烷基、C₃ 烷基、C₄ 烷基、C₅ 烷基、C₆ 烷基、C₁ -C₂ 烷基、C₂ 烷基、C₃ 烷基、C₁ -C₃ 烷基、C₁ -C₄ 烷基、C₁ -C₅ 烷基、C₁ -C₆ 烷基、C₂ -C₃ 烷基、C₂ -C₄ 烷基、C₂ -C₅ 烷基、C₂ -C₆ 烷基、C₃ -C₄ 烷基、C₃ -C₅ 烷基、C₃ -C₆ 烷基、C₄ -C₅ 烷基、C₄ -C₆ 烷基、C₅ -C₆ 烷基及C₆ 烷基。儘管應理解，取代在任何可用原子處連接以產生穩定化合物，但當視情況經取代之烷基為諸如-OR（例如烷氧基）、-SR（例如硫烷基）、-NHR（例如烷胺基）、-C(O)NHR及其類似物之部分之R基團時，烷基R基團之取代使得結合至該部分之任何O、S或N（除其中N為雜芳基環原子以外）之烷基碳之取代排除將引起取代基之任何O、S或N（除其中N為雜芳基環原子以外）與結合至該部分之任何O、S或N之烷基碳結合之取代基。Unless otherwise specified, "alkyl" alone or as part of another substituent means a straight or branched chain hydrocarbon having the specified number of carbon atoms (ie, C1 _{- C6} means one to six carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Other representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl base and the like. For each of the definitions herein (eg, alkyl, alkoxy, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, etc.), without including the prefix to When indicating the number of carbon atoms in an alkyl moiety, the alkyl moiety or portion thereof has 12 or fewer backbone carbon atoms, or 8 or fewer backbone carbon atoms, or 6 or fewer backbone carbon atoms carbon atom. For example, C ₁ -C ₆ alkyl refers to straight or branched chain hydrocarbons having 1, 2, 3, 4, 5 or 6 carbon atoms, including but not limited to -CH ₃ , C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, C ₆ alkyl, C ₁ -C ₂ alkyl, C ₂ alkyl, C ₃ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₄ Alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₃ alkyl, C ₂ -C ₄ alkyl, C ₂ -C ₅ alkyl, C ₂ -C ₆ alkyl , C ₃ -C ₄ alkyl, C ₃ -C ₅ alkyl, C ₃ -C ₆ alkyl, C ₄ -C ₅ alkyl, C ₄ -C ₆ alkyl, C ₅ -C ₆ alkyl and C ₆ alkyl. While it should be understood that substitutions are attached at any available atom to produce stable compounds, when optionally substituted alkyl groups such as -OR (eg, alkoxy), -SR (eg, sulfanyl), -NHR (eg, alkoxy) amine), -C(O)NHR and their analogs, the substitution of the alkyl R group is such that any O, S, or N bound to the moiety (except where N is a heteroaryl ring) The exclusion of substitution of an alkyl carbon other than atom) would result in any O, S or N of the substituent (other than where N is a heteroaryl ring atom) being bound to any O, S or N alkyl carbon bound to the moiety the substituent.

單獨或作為另一取代基之一部分之「伸烷基」意謂衍生自具有前綴中所指示之碳原子數目之烷烴之直鏈或分支鏈飽和二價烴部分。舉例而言，（亦即C_1- C₆ 意謂一至六個碳；C_1- C₆ 伸烷基意謂包括亞甲基、伸乙基、伸丙基、2-甲基伸丙基、伸戊基、伸己基及其類似基團）。C_1-‑4 伸烷基包括亞甲基-CH₂ -、伸乙基-CH₂ CH2-、伸丙基-CH₂ CH₂ CH₂ -，及伸異丙基-CH(CH₃ )CH₂ ‑、-CH₂ CH(CH₃ )-、-CH₂ -(CH₂ )₂ CH₂ -、-CH₂ -CH(CH₃ )CH₂ -、-CH₂ -C(CH₃ )₂ -CH₂ -CH₂ CH(CH₃ )-。通常，烷基（或伸烷基）將具有1至24個碳原子，以及具有10個或更少的、8個或更少的或6個或更少的碳原子之彼等基團。當不包括用於指示伸烷基部分中之碳原子數目之前綴時，伸烷基部分或其一部分將具有12個或更少的主鏈碳原子，或8個或更少的主鏈碳原子、6個或更少的主鏈碳原子，或4個或更少的主鏈碳原子，或3個或更少的主鏈碳原子，或2個或更少的主鏈碳原子，或1個碳原子。"Alkylene" alone or as part of another substituent means a straight or branched chain saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e. C _1- C ₆ means one to six carbons; C _1- C ₆ alkylene means including methylene, ethylidene, propylidene, 2-methylpropylidene, pentyl, hexyl and similar groups). C _1--4 alkylene groups include methylene _- CH2-, ethylidene-CH2CH2-, propylidene- _CH2CH2CH2- , and isopropylidene- _CH ( _{CH3 ) CH 2} ‑, -CH ₂ CH(CH ₃ )-, -CH ₂ -(CH ₂ ) ₂ CH ₂ -, -CH ₂ -CH(CH ₃ )CH ₂ -, -CH ₂ -C(CH ₃ ) ₂ - _{CH2 -} CH2CH( _CH3 )-. Typically, an alkyl group (or alkylene group) will have 1 to 24 carbon atoms, and those groups having 10 or less, 8 or less, or 6 or less carbon atoms. When the prefix used to indicate the number of carbon atoms in the alkylene moiety is not included, the alkylene moiety or a portion thereof will have 12 or fewer backbone carbon atoms, or 8 or fewer backbone carbon atoms , 6 or less backbone carbon atoms, or 4 or less backbone carbon atoms, or 3 or less backbone carbon atoms, or 2 or less backbone carbon atoms, or 1 carbon atoms.

「烯基」係指具有前綴中所指示之碳原子數目且含有至少一個雙鍵之直鏈單價烴基或分支鏈單價烴基。舉例而言，C₂ -C₆ 烯基意謂包括乙烯基、丙烯基及其類似物。「C₂ -C₆ 烯基C₁ -C₆ 伸烷基」為基團-C₁ -C₆ 伸烷基-C₂ -C₆ 烯基，其中烯基及伸烷基係如本文中所定義。"Alkenyl" refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, C2 _{- C6} alkenyl is meant to include vinyl, propenyl, and the like. "C ₂ -C ₆ alkenyl C ₁ -C ₆ alkylene" is the group -C ₁ -C ₆ alkylene-C ₂ -C ₆ alkenyl, wherein alkenyl and alkylene are as defined herein definition.

術語「伸烯基」係指含有至少一個雙鍵且具有前綴中所指示之碳原子數目之直鏈二價烴基或分支鏈二價烴基。此等基團之實例包括乙烯基、2-丙烯基、巴豆基（crotyl）、2-異戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)，及高碳同系物及異構體。The term "alkenylene" refers to a straight or branched divalent hydrocarbon group containing at least one double bond and having the number of carbon atoms indicated in the prefix. Examples of such groups include vinyl, 2-propenyl, crotyl, 2-prenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 , 4-pentadienyl), and higher carbon homologues and isomers.

術語「炔基」係指單價不飽和烴，在一些實施例中，其具有2至20個碳原子（在一些實施例中，2至10個碳原子，例如2至6個碳原子）且具有1至6個碳-碳參鍵，例如1、2或3個碳-碳參鍵。在一些實施例中，炔基包括乙炔基（-C≡CH）、炔丙基（或丙炔基，例如-C≡CCH₃ ）及其類似者。在烯基或炔基部分不包括指示碳原子數目之前綴時，烯基或炔基部分或其一部分將具有12個或更少的主鏈碳原子，或8個或更少的主鏈碳原子、6個或更少的主鏈碳原子或4個或更少的主鏈碳原子。The term "alkynyl" refers to a monovalent unsaturated hydrocarbon, in some embodiments, having 2 to 20 carbon atoms (in some embodiments, 2 to 10 carbon atoms, eg, 2 to 6 carbon atoms) and having 1 to 6 carbon-carbon bonds, eg 1, 2 or 3 carbon-carbon bonds. In some embodiments, alkynyl groups include ethynyl (-C≡CH), propargyl (or propynyl, eg, -C≡CCH ₃ ), and the like. When the alkenyl or alkynyl moiety does not include a prefix indicating the number of carbon atoms, the alkenyl or alkynyl moiety or a portion thereof will have 12 or fewer backbone carbon atoms, or 8 or fewer backbone carbon atoms , 6 or fewer backbone carbon atoms, or 4 or fewer backbone carbon atoms.

術語「伸炔基」係指含有至少一個參鍵且具有前綴中所指示之碳原子數目之直鏈二價烴基或分支鏈二價烴基。此等基團之實例包括乙炔基、1-及3-丙炔基、3-丁炔基及高碳同源物及異構體。The term "alkynylene" refers to a straight-chain divalent hydrocarbon group or a branched-chain divalent hydrocarbon group containing at least one double bond and having the number of carbon atoms indicated in the prefix. Examples of such groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher carbon homologues and isomers.

「烷氧基（alkoxy/alkoxyl）」係指-O-烷基，其中烷基係如本文中所定義。作為實例，「C₁ -C₆ 烷氧基」係指-O-C₁ -C₆ 烷基，其中烷基係如本文中所定義。儘管應理解，烷氧基上之取代在任何可用的原子處連接以產生穩定化合物，但烷氧基之取代應使得O、S或N（除其中N為雜芳基環原子以外）不與結合至烷氧基O之烷基碳結合。此外，當烷氧基經描述為另一部分之取代基時，烷氧基氧不與結合至另一部分之O、S或N（除其中N為雜芳基環原子以外）或另一部分之烯烴或炔烴碳之碳原子結合。"alkoxy/alkoxyl" refers to -O-alkyl, wherein alkyl is as defined herein. As an example, " _C1 -C6alkoxy" refers to _{-OC1-C6 alkyl ,} wherein alkyl is as defined herein. While it is understood that substitution on an alkoxy group is attached at any available atom to produce stable compounds, substitution on an alkoxy group should be such that O, S or N (except where N is a heteroaryl ring atom) does not bind to Alkyl carbon bond to alkoxy O. Furthermore, when an alkoxy group is described as a substituent of another moiety, the alkoxy oxygen does not bind to O, S or N (other than where N is a heteroaryl ring atom) of the other moiety or an alkene of the other moiety or Alkyne carbons are bonded to carbon atoms.

術語「烷氧基烷基」及「烷氧基伸烷基」係指經烷氧基取代之烷基。作為實例，「C₁ -C₆ 烷氧基C₁ -C₆ 烷基」係指經C₁ -C₆ 烷氧基取代之C₁ -C₆ 烷基，其中烷基及烷氧基係如本文中所定義，而「C₁ -C₃ 烷氧基C₁ -C₃ 伸烷基」係指經C₁ -C₃ 烷氧基取代之C₁ -C₃ 烷基，其中伸烷基及烷氧基係如本文中所定義。The terms "alkoxyalkyl" and "alkoxyalkylene" refer to an alkyl group substituted with an alkoxy group. As an example, "C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl" refers to C ₁ -C ₆ alkyl substituted with C ₁ -C ₆ alkoxy, wherein the alkyl and alkoxy groups are such as As defined herein, "C ₁ -C ₃ alkoxy C ₁ -C ₃ alkylene" refers to C ₁ -C ₃ alkyl substituted with C ₁ -C ₃ alkoxy, wherein alkylene and Alkoxy is as defined herein.

「胺基」或「胺」表示基團-NH₂ 。"Amine" or "amine" means the group _-NH2 .

除非另外說明，否則「芳基」本身或作為另一取代基之一部分係指含有6至14個環碳原子之單環、雙環或多環多不飽和芳族烴自由基，其可以為單個環或稠合在一起或共價連接之多個環（至多三個環）。然而，芳基不以任何方式涵蓋下文所定義之雜芳基或與其重疊。若一或多個芳基環與雜芳基環稠合，則所得環系統為雜芳基。未經取代之芳基之非限制性實例包括苯基、1-萘基及2-萘基。術語「伸芳基」係指二價芳基，其中芳基係如本文中所定義。Unless otherwise specified, "aryl" by itself or as part of another substituent refers to a monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical containing 6 to 14 ring carbon atoms, which may be a single ring Or multiple rings (up to three rings) fused together or covalently linked. However, aryl does not in any way encompass or overlap with heteroaryl as defined below. If one or more aryl rings are fused to a heteroaryl ring, the resulting ring system is a heteroaryl. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term "arylidene" refers to a divalent aryl group, wherein aryl is as defined herein.

「5-6員芳族環」係指如本文所定義之苯環或5-6員雜芳基環。出於本發明之目的，橋頭原子不能在任何特定環上為兩個相鄰原子。"5-6 membered aromatic ring" refers to a benzene ring or a 5-6 membered heteroaryl ring as defined herein. For the purposes of the present invention, bridgehead atoms cannot be two adjacent atoms on any given ring.

「橋接環」或「橋接化合物」係具有兩個或兩個以上環之碳環或雜環化合物或部分，該等環含有連接兩個橋頭原子之一個至四個碳原子的橋。在本發明中，片語「橋接碳環或雜環」具有與片語「橋接羧基環或橋接雜環」相同之含義。出於本發明之目的，橋接環中之兩個橋頭原子無法在任何特定環上具有相同原子。橋接雜環係指具有至少一個雜原子之橋接化合物。橋頭原子係分子骨架構架之一部分。橋接環（或化合物）可為完全碳環（所有碳骨架原子）。以下為橋接環之實例，展示了每個橋原子及橋頭原子。

A "bridged ring" or "bridged compound" is a carbocyclic or heterocyclic compound or moiety having two or more rings containing a bridge connecting one to four carbon atoms from one of the two bridgehead atoms. In the present invention, the phrase "bridged carbocycle or heterocycle" has the same meaning as the phrase "bridged carboxyl ring or bridged heterocycle". For the purposes of the present invention, two bridgehead atoms in a bridged ring cannot have the same atom on any particular ring. A bridged heterocycle refers to a bridged compound having at least one heteroatom. The bridgehead atom is part of the molecular skeleton. A bridged ring (or compound) can be a fully carbocyclic ring (all carbon backbone atoms). The following is an example of a bridged ring, showing each bridge atom and the bridgehead atom.

出於本發明之目的，橋接環意謂包括可視情況具有1-2個C₁ -C₃ 烷基之環，其不連接於其橋原子及橋頭原子上，且此等橋接環可以如本發明中所描述經取代。橋接環之其他非限制性實例包括雙環[1.1.1]戊烷、金剛烷基、(1s,5s)-雙環[3.3.1]壬烷、(1R,5S)-6,6-二甲基雙環[3.1.1]庚烷、（1R,5S）-6,6-二甲基雙環[3.1.1]庚烷、(1r,2R,4S,5r,6R,8S)-四環[3.3.1.02,4.06,8]壬烷、雙環[2.2.1庚烷、雙環[2.2.2]辛烷及1-氟雙環[2.2.2]辛烷。For the purposes of the present invention, bridged rings are meant to include rings optionally having _1-2 C1 _- C3 alkyl groups, which are not attached to their bridge atoms and bridgehead atoms, and such bridged rings may be as in the present invention Substituted as described in . Other non-limiting examples of bridged rings include bicyclo[1.1.1]pentane, adamantyl, (1s,5s)-bicyclo[3.3.1]nonane, (1R,5S)-6,6-dimethyl Bicyclo[3.1.1]heptane, (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptane, (1r,2R,4S,5r,6R,8S)-tetracyclo[3.3. 1.02,4.06,8]nonane, bicyclo[2.2.1heptane, bicyclo[2.2.2]octane and 1-fluorobicyclo[2.2.2]octane.

除非另外說明，否則「環烷基」或「碳環」或「碳環狀」本身或作為另一取代基之部分係指飽和或部分不飽和、非芳族單環或稠環，諸如雙環或三環碳環系統，或立方烷，其具有前綴中所指示之碳原子數目或若非特定，則具有36個、亦46個且亦5-6個環成員，諸如環丙基、環戊基、環己基，其中一個或兩個環碳原子可視情況由羰基置換。此外，術語環烷基意欲涵蓋與（例如芳基之）芳族環稠合之環系統，而與分子之其餘部分之連接點無關。環烷基係指具有指示數目之環原子之烴環（例如C_3-6 環烷基及3-6員環烷基皆意謂三至六個環碳原子）。術語「環烯基」係指具有至少一個不飽和單元之環烷基。環烷基或環烯基之取代基可位於環烷基或環烯基之連接點，形成四級中心。Unless otherwise specified, "cycloalkyl" or "carbocycle" or "carbocyclic" by itself or as part of another substituent refers to a saturated or partially unsaturated, non-aromatic monocyclic or fused ring, such as a bicyclic or A tricyclic carbocyclic ring system, or cubic alkane, has the number of carbon atoms indicated in the prefix or, if not specified, 36, also 46, and also 5-6 ring members, such as cyclopropyl, cyclopentyl, Cyclohexyl wherein one or two ring carbon atoms are optionally replaced by carbonyl. Furthermore, the term cycloalkyl is intended to encompass ring systems fused to an aromatic ring, such as that of aryl, regardless of the point of attachment to the rest of the molecule. Cycloalkyl refers to a hydrocarbon ring having the indicated number of ring atoms (eg, C _3-6 cycloalkyl and 3-6 membered cycloalkyl both mean three to six ring carbon atoms). The term "cycloalkenyl" refers to a cycloalkyl group having at least one unit of unsaturation. Substituents to a cycloalkyl or cycloalkenyl group may be located at the point of attachment of the cycloalkyl or cycloalkenyl group, forming a quaternary center.

「環烷基烷基」及「環烷基伸烷基」係指-(伸烷基)-環烷基，其中如本文中所定義之伸烷基具有所指示數目之碳原子或若非特定，則具有六個或更少的碳原子；且如本文中所定義之環烷基具有所指示數目之碳原子或若非特定，則每個環具有310個，亦38個，及亦36個環成員。作為實例，4-6員環烷基-C₁ -C₆ 烷基係指連接至具有1-6個碳原子之伸烷基鏈之具有4-6個碳原子之環烷基，其中伸烷基鏈連接至母體部分。其他例示性環烷基烷基包括例如環丙基亞甲基、環丁基伸乙基、環丁基亞甲基及其類似基團。「環烷基伸炔基」係指-(伸炔基)-環烷基，舉例而言C₃ -C₆ 環烷基C₂ -C₆ 伸炔基為基團-(C₂ -C₆ 伸炔基)-C₃ -C₆ 環烷基。「C₃ -C₆ 環烷基伸乙炔基」為基團-C≡C-C₃ -C₆ 環烷基。"Cycloalkylalkyl" and "cycloalkylalkylene" refer to -(alkylene)-cycloalkyl, wherein alkylene, as defined herein, has the indicated number of carbon atoms or, if not specified, having six or fewer carbon atoms; and cycloalkyl as defined herein has the indicated number of carbon atoms or, if not specified, 310, also 38, and also 36 ring members per ring. As an example, a 4-6 membered cycloalkyl-Ci _{- C6} alkyl refers to a cycloalkyl group of 4-6 carbon atoms attached to an alkylene chain of 1-6 carbon atoms, wherein the alkylene The base chain is attached to the parent moiety. Other exemplary cycloalkylalkyl groups include, for example, cyclopropylmethylene, cyclobutylethylidene, cyclobutylmethylene, and the like. "Cycloalkylalkynylene" means -(alkynylene)-cycloalkyl, for example C3 _- C6cycloalkylC2 _{- C6alkynylene} is the group _- (C2 _{- C6alkynylene} ) alkynyl) _{-C3 -} C6cycloalkyl. "C ₃ -C ₆ cycloalkylethynylene" is the group -C≡CC ₃ -C ₆ cycloalkyl.

術語「氰基」係指基團-CN。術語「C₁ -C₆ 氰烷基」係指經1、2或3個氰基取代之如本文中所定義之C₁ -C₆ 烷基。「C₁ -C₆ 氰烷基伸乙炔基」為基團-C≡C-C₁ -C₆ 氰烷基。The term "cyano" refers to the group -CN. The term " _C1 - _C6 cyanoalkyl" refers to a _C1 - _C6 alkyl group, as defined herein, substituted with 1, 2 or 3 cyano groups. "C ₁ -C ₆ cyanoalkylethynylene" is the group -C≡CC ₁ -C ₆ cyanoalkyl.

術語「鹵烷基」係指經一至七個鹵素原子取代之烷基。鹵烷基包括單鹵烷基或聚鹵烷基。舉例而言，術語「C₁ -C₆ 鹵烷基」意謂包括三氟甲基、二氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基及其類似物。此外，術語「鹵伸烷基」係指經一至七個鹵素原子取代之伸烷基。The term "haloalkyl" refers to an alkyl group substituted with one to seven halogen atoms. Haloalkyl groups include monohaloalkyl groups or polyhaloalkyl groups. For example, the term " _C1 - _C6 haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and its analogs. Furthermore, the term "haloalkylene" refers to an alkylene group substituted with one to seven halogen atoms.

術語「鹵烷氧基（haloalkoxy/haloalkoxyl）」係指a-O-鹵烷基，其中鹵烷基如本文中所定義。鹵素烷氧基包括單鹵烷氧基或聚鹵烷氧基。舉例而言，術語「C₁ -C₆ 鹵烷氧基」意謂包括三氟甲氧基、二氟甲氧基及其類似物。The term "haloalkoxy/haloalkoxyl" refers to aO-haloalkyl, wherein haloalkyl is as defined herein. Haloalkoxy includes monohaloalkoxy or polyhaloalkoxy. For example, the term "Ci _{- C6} haloalkoxy" is meant to include trifluoromethoxy, difluoromethoxy, and the like.

「鹵素」或「鹵基」係指所有鹵素，亦即氯（Cl）、氟(F)、溴（Br）或碘（I）。"Halogen" or "halo" refers to all halogens, ie chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).

「雜原子」意謂包括氧（O）、氮（N）及硫（S）。"Heteroatom" is meant to include oxygen (O), nitrogen (N) and sulfur (S).

「雜芳基」係指含有5-9個環原子之單環或雙環芳族環自由基（在本發明中亦稱為5-9員雜芳基），包括含有5或6個環原子之單環芳族環自由基（在本發明中亦稱為5-6員雜芳基），其含有獨立地選自由以下組成之組之一或多個、14個、13個或12個雜原子：O、S及N。含有至少一個雜原子之任何芳族環或環系統皆為雜芳基而與連接點無關（亦即，經由稠環中之任一者）。雜芳基亦意欲包括經氧化之S或N，諸如亞磺醯基、磺醯基及第三環氮之N-氧化物。碳或氮原子為使得產生穩定化合物之雜芳基環結構之連接點。雜芳基之實例包括（但不限於）吡啶基、嗒

基、吡

基、吲哚

基、苯并[b]噻吩基、喹唑啉基、嘌呤基、吲哚基、喹啉基、嘧啶基、吡咯基、吡唑基、

唑基、噻唑基、噻吩基、異

唑基、

噻二唑基、異噻唑基、四唑基、咪唑基、***基、呋喃基、苯并呋喃基、三

基、喹喏啉基、

啉基、呔

基、苯并三

基、苯并咪唑基、苯并吡唑基、苯并***基、苯并異

唑基、異苯并呋喃基、異吲哚基、吲哚

基、苯并三

基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑吡啶、苯并噻唑基、苯并噻吩基、喹啉基、異喹啉基、吲唑基、喋啶基及噻二唑基。「含氮雜芳基」係指其中至少一個環雜原子為N之雜芳基。"Heteroaryl" means a monocyclic or bicyclic aromatic ring radical containing 5-9 ring atoms (also referred to as a 5-9 membered heteroaryl in the present invention), including those containing 5 or 6 ring atoms A monocyclic aromatic ring radical (also referred to in the present invention as a 5-6 membered heteroaryl) containing one or more, 14, 13 or 12 heteroatoms independently selected from the group consisting of : O, S and N. Any aromatic ring or ring system containing at least one heteroatom is heteroaryl regardless of the point of attachment (ie, via any of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and the N-oxide of the third ring nitrogen. The carbon or nitrogen atom is the point of attachment that results in the heteroaryl ring structure of the stable compound. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridyl

base, pyridine

base, indole

base, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl,

azolyl, thiazolyl, thienyl, iso

azolyl,

Thiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furyl, benzofuranyl, triazolyl

base, quinolinyl,

Linyl, sulfonated

base, benzotri

base, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benziso

azolyl, isobenzofuranyl, isoindolyl, indole

base, benzotri

base, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, indazolyl, pteridyl and thiadi azolyl. "Nitrogen-containing heteroaryl" refers to a heteroaryl group in which at least one ring heteroatom is N.

「雜環烷基」係指含有一至五個選自N、O、S（包括S(O)及S(O)₂ ）或P（包括氧化膦）之雜原子之飽和或部分不飽和非芳族環烷基，其中氮、硫及磷原子視情況經氧化，且氮原子視情況經四級化，其餘環原子為C，其中一個或兩個C原子可視情況以羰基形式存在。此外，術語雜環烷基意欲涵蓋任何含有至少一個不為雜芳基之雜原子之環或環系統，而與分子之其餘部分之連接點無關。雜環烷基包括具有環之彼等基團，該環具有形式上電荷分離之芳族共振結構，例如N-甲基吡啶基。雜環烷基可經一個或兩個側氧基取代，且可以包括碸及亞碸衍生物。雜環烷基可為具有3至12個、4至10個、5至10個或5至6個環原子之單環、稠合雙環或稠合多環系統，其中一至五個環原子為選自-N=、-N-、-O-、-S-、-S(O)-或-S(O)₂ -之雜原子，且此外其中一個或兩個環原子視情況由-C(O)-基團置換。作為實例，4-6員雜環烷基為具有至少一個雜原子之具有4-6個環成員之雜環烷基。雜環烷基亦可以為與環烷基稠合之雜環烷基環。雜環烷基之非限制性實例包括吡咯啶基、哌啶基、

啉基、吡啶酮基及其類似物。雜環基可以經由環碳或雜原子連接至分子之其餘部分。「雜環烯基」係指具有至少一個不飽和單元之雜環烷基。雜環烷基或雜環烯基之取代基可位於雜環烷基或雜環烯基之連接點，形成四級中心。"Heterocycloalkyl" means a saturated or partially unsaturated non-aryl group containing one to five heteroatoms selected from N, O, S (including S(O) and S(O) ₂ ) or P (including phosphine oxides) Cycloalkyl in which the nitrogen, sulfur and phosphorus atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, one or both of which are optionally present as carbonyl groups. Furthermore, the term heterocycloalkyl is intended to encompass any ring or ring system containing at least one heteroatom that is not heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those groups having a ring with formally charge-separated aromatic resonance structures, such as N-picoline. Heterocycloalkyl groups can be substituted with one or two pendant oxy groups, and can include thionite and thionite derivatives. Heterocycloalkyl can be a monocyclic, fused bicyclic, or fused polycyclic ring system having 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, wherein one to five ring atoms are selected heteroatoms from -N=, -N-, -O-, -S-, -S(O)- or -S(O) _2- , and in addition one or both of the ring atoms are optionally represented by -C( O)-group replacement. As an example, a 4-6 membered heterocycloalkyl is a heterocycloalkyl having 4-6 ring members with at least one heteroatom. A heterocycloalkyl group can also be a heterocycloalkyl ring fused to a cycloalkyl group. Non-limiting examples of heterocycloalkyl include pyrrolidinyl, piperidinyl,

Lino, pyridone and their analogs. A heterocyclyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. "Heterocycloalkenyl" refers to a heterocycloalkyl group having at least one unit of unsaturation. A heterocycloalkyl or heterocycloalkenyl substituent may be located at the point of attachment of the heterocycloalkyl or heterocycloalkenyl, forming a quaternary center.

「羥基（Hydroxyl/hydroxy）」係指基團OH。術語「羥基烷基」或「羥基伸烷基」係分別指經1-5個羥基取代之如本文中所定義之烷基或伸烷基。"Hydroxyl/hydroxy" refers to the group OH. The terms "hydroxyalkyl" or "hydroxyalkylene" refer to an alkyl or alkylene group, respectively, as defined herein, substituted with 1-5 hydroxy groups.

術語「側氧基」係指C(=O)或(O)。在一些實施例中，碳上之兩個可能的連接點形成側氧基。The term "pendant oxy" refers to C(=O) or (O). In some embodiments, two possible points of attachment on the carbon form pendant oxygen groups.

如貫穿本發明使用之「視情況選用之取代基」或「視情況經取代」意謂化合物上之取代可能存在或可能不存在，且說明書包括其中存在取代之實例及其中不存在取代之實例。舉例而言，片語「視情況經1-3個T¹ 基團取代」意謂可但無需存在T¹ 基團。在本發明中，假設化合物上之視情況存在之取代以將產生穩定化合物之方式進行。As used throughout this disclosure, "optionally substituted" or "optionally substituted" means that substitution on a compound may or may not be present, and the specification includes instances where substitution is present and instances where substitution is absent. For example, the phrase "optionally substituted with ^1-3 T1 groups" means that ^a T1 group may but need not be present. In the present invention, it is assumed that optional substitutions on compounds are made in a manner that will result in stable compounds.

「螺碳原子」係兩個環共有之碳原子。「碳環螺環」包含在一個共同螺碳原子處連接之兩個環烷基環，如此實例中所示：

。「雜環螺環」包含在一個共同螺碳原子處連接至雜環之環烷基或雜環烷基環，如此實例中所示：

。A "spirocarbon atom" is a carbon atom common to both rings. A "carbocyclic spirocycle" comprises two cycloalkyl rings joined at a common spiro carbon atom, as shown in this example:

. A "heterocyclic spirocycle" includes a cycloalkyl or heterocycloalkyl ring attached to a heterocycle at a common spiro carbon atom, as shown in this example:

.

如本文中關於本發明之化合物所使用，術語「合成」及類似術語意謂由一或多種前驅物材料化學合成。As used herein with respect to the compounds of the present invention, the term "synthesis" and similar terms means chemical synthesis from one or more precursor materials.

如本文所使用，術語「組合物」係指適於向吾人所需動物個體投與以用於治療目的之調配物，其含有至少一種醫藥學活性化合物及至少一種醫藥學上可接受之載劑或賦形劑。As used herein, the term "composition" refers to a formulation suitable for administration to an animal subject in our need for therapeutic purposes, comprising at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipients.

術語「醫藥學上可接受之」指示在考慮待治療之疾病或病況及各別投與途徑的情況下，所指示之物質不具有將使相當謹慎之醫學從業者避免向患者投與該物質之特性。舉例而言，通常需要此類物質為基本上無菌的，例如用於可注射劑。The term "pharmaceutically acceptable" indicates that, taking into account the disease or condition to be treated and the respective route of administration, the indicated substance has no potential to cause a reasonably prudent medical practitioner to avoid administering the substance to a patient. characteristic. For example, it is often desirable for such materials to be substantially sterile, eg, for injectable formulations.

「醫藥學上可接受之鹽」係指可接受投與患者（諸如哺乳動物）之鹽（例如對於既定劑量療法，具有可接受之哺乳動物安全性之鹽）。所涵蓋之醫藥學上可接受之鹽形式包括（但不限於）單、雙、參、肆等。醫藥學上可接受之鹽在其投與量及濃度下為無毒的。此類鹽之製備可以藉由在不阻礙化合物發揮其生理學作用的情況下改變其物理特徵而便於藥理學使用。物理特性之適用變化包括降低熔點以便於經黏膜投與及提高溶解性以便於投與較高濃度之藥物。此類鹽可以來源於醫藥學上可接受之無機鹼或有機鹼及來自醫藥學上可接受之無機酸或有機酸，視在本文中所描述之化合物上發現的特定取代基而定。"Pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (eg, a salt with acceptable mammalian safety for a given dose of therapy). The pharmaceutically acceptable salt forms encompassed include, but are not limited to, mono, di, ginseng, tetra, and the like. Pharmaceutically acceptable salts are nontoxic in the amounts and concentrations at which they are administered. Such salts can be prepared to facilitate pharmacological use by altering the physical characteristics of the compound without preventing it from exerting its physiological effect. Suitable changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein.

醫藥學上可接受之鹽可以藉由標準技術製備。舉例而言，化合物之游離鹼形式可以溶解於適合的溶劑（諸如含有適合的酸之水溶液或水-醇溶液）中且隨後藉由蒸發溶液來分離。在另一實例中，鹽可以藉由使游離鹼及酸在有機溶劑中反應來製備。Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous or hydro-alcoholic solution containing a suitable acid and subsequently isolated by evaporation of the solution. In another example, salts can be prepared by reacting the free base and acid in an organic solvent.

當本發明之化合物含有相對酸性官能基時，可以藉由使此類化合物之中性形式與純淨的或在適合的惰性溶劑中之足量的所需鹼（亦即，一級、二級、三級、四級或環胺；鹼金屬氫氧化物；鹼土金屬氫氧化物；或其類似物）接觸來獲得鹼加成鹽。所需酸可以為例如哌喃糖酸（諸如葡糖醛酸或半乳糖醛酸）、α-羥基酸（諸如檸檬酸或酒石酸）、胺基酸（諸如天冬胺酸或麩胺酸）、芳族酸（諸如苯甲酸或肉桂酸）、磺酸（諸如對甲苯磺酸或乙磺酸）或其類似物。在一些實施例中，鹽可衍生自醫藥學上可接受之酸，諸如乙酸、三氟乙酸、丙酸、抗壞血酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、反丁烯二酸、乙醇酸、葡萄糖酸、葡糖醛酸、麩胺酸、馬尿酸、氫溴酸、鹽酸、羥乙基磺酸、乳酸、乳糖酸、順丁烯二酸、蘋果酸、丙二酸、杏仁酸、草酸、甲烷磺酸、黏液酸、萘磺酸、菸鹼酸、硝酸、雙羥萘酸、泛酸、磷酸、丁二酸、硫酸、胺磺酸、氫碘酸、碳酸、酒石酸、對甲苯磺酸、丙酮酸、天冬胺酸、苯甲酸、肉桂酸、鄰胺基苯甲酸、甲磺酸、柳酸、對羥基苯甲酸、苯乙酸、恩波酸（帕莫酸）（雙羥萘酸）、乙烷磺酸、苯磺酸、2-羥基乙磺酸、對胺基苯磺酸、硬脂酸、環己基胺磺酸、環己胺基磺酸、奎尼酸、褐藻酸、羥基丁酸、半乳糖二酸及半乳糖醛酸以及類似物。When the compounds of the present invention contain relatively acidic functional groups, they can be obtained by combining such compounds in their neutral form with a sufficient amount of the desired base (ie, primary, secondary, tertiary, pure or in a suitable inert solvent) primary, quaternary or cyclic amine; alkali metal hydroxide; alkaline earth metal hydroxide; or the like) to obtain a base addition salt. Desired acids can be, for example, piperanonic acids (such as glucuronic or galacturonic acids), alpha-hydroxy acids (such as citric or tartaric acids), amino acids (such as aspartic or glutamic acids), Aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), or the like. In some embodiments, salts can be derived from pharmaceutically acceptable acids such as acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid Oleic acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid acid, mandelic acid, oxalic acid, methanesulfonic acid, mucilic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, sulfamic acid, hydroiodic acid, carbonic acid, tartaric acid , p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embolic acid (Pamoic acid) ( Pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, stearic acid, cyclohexylaminesulfonic acid, cyclohexylaminosulfonic acid, quinic acid, Alginic acid, hydroxybutyric acid, galacturonic acid and galacturonic acid and the like.

亦包括胺基酸（諸如精胺酸及其類似物）之鹽，及有機酸（如葡糖醛酸或半乳糖醛酸及其類似物）之鹽（參見例如Berge, S. M等人, 「醫藥鹽（Pharmaceutical Salts）」, 《醫藥科學雜誌（J. Pharmaceutical Science）》, 1977, 66:1-19）。本發明之某些特定化合物含有允許該等化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基兩者。Also included are salts of amino acids such as arginine and its analogs, and salts of organic acids such as glucuronic or galacturonic acids and their analogs (see, e.g., Berge, S. M. et al., "Pharmaceutical Salts", J. Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

中性形式之化合物可藉由使鹽與鹼或酸接觸且以習知方式分離母體化合物而再生。化合物之母體形式與各種鹽形式之不同之處在於某些物理特性，例如在極性溶劑中之溶解性，但出於本發明之目的，在其他方面，該等鹽等效於化合物之母體形式。The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are otherwise equivalent to the parent form of the compound.

不同化合物之醫藥學上可接受之鹽可以複合物形式存在。複合物之實例包括8-氯茶鹼複合物（與例如茶苯海明（dimenhydrinate）:苯海拉明（diphenhydramine）8-氯茶鹼（1:1）複合物類似；暈海寧（Dramamine））及各種環糊精包合複合物。Pharmaceutically acceptable salts of different compounds may exist in complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, eg, dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) And various cyclodextrin inclusion complexes.

如本文所使用，單獨或作為基團之一部分之術語「氘化」意謂經取代之氘原子。如本文所使用，單獨或作為基團之一部分之術語「氘代類似物」意謂含有代替氫原子之經取代之氘原子的化合物。本發明之氘代類似物可為完全或部分經氘取代之衍生物。在一些實施例中，本發明之經氘取代之衍生物具有完全或部分經氘取代之烷基、芳基或雜芳基。As used herein, the term "deuterated" alone or as part of a group means a substituted deuterium atom. As used herein, the term "deuterated analog" alone or as part of a group means a compound containing a substituted deuterium atom in place of a hydrogen atom. The deuterated analogs of the present invention may be fully or partially deuterium substituted derivatives. In some embodiments, the deuterium-substituted derivatives of the present invention have fully or partially deuterium-substituted alkyl, aryl, or heteroaryl groups.

本發明亦涵蓋經同位素標記之本發明之化合物，其等同於本文中所列舉之彼等化合物，但事實上一或多個原子經原子質量或質量數與自然界中通常發現的原子質量或質量數不同之原子置換。本發明之化合物之所有同位素變體無論是否為放射性均意欲涵蓋於本發明之範疇內。可併入本發明之化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素，諸如（但不限於）² H （氘，D）、³ H （氚）、¹¹ C、¹³ C、¹⁴ C、¹⁵ N、¹⁸ F、³¹ P、³² P、³⁵ S、³⁶ Cl及¹²⁵ I。除非另外說明，否則當一個位置特定地指定為「H」或「氫」時，該位置應理解為在其天然豐度同位素組成或其同位素（諸如氘（D）或氚（³ H））中具有氫。本發明之某些經同位素標記之化合物（例如經³ H或¹⁴ C標記之化合物）適用於化合物及/或底物組織分佈分析法。氚化（亦即，³ H）及碳-14（亦即，¹⁴ C）及氟-18（¹⁸ F）同位素因其易於製備及可偵測性而適用。此外，用諸如氘（亦即，² H）之較重同位素取代可得到某些由更高代謝穩定性產生之治療優點（例如增加之活體內半衰期或降低之劑量需求）且因此在一些情況下為較佳的。經同位素標記之本發明之化合物通常可以藉由根據與在下文中之流程及實例中所描述之彼等程序類似的程序，用經同位素標記之試劑取代未經同位素標記之試劑來製備。The present invention also encompasses isotopically-labeled compounds of the present invention that are equivalent to those compounds recited herein, except that in fact one or more atoms have an atomic mass or mass number that differs from the atomic mass or mass number commonly found in nature different atomic substitutions. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, ^2H (deuterium, D), ^3H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to be in its natural abundance isotopic composition or its isotopes such as deuterium (D) or tritium ( ^3H ) Has hydrogen. Certain isotopically-labeled compounds of the invention (eg, ^3H or ^14C -labeled compounds) are suitable for use in compound and/or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) and fluorine-18 ( ¹⁸ F) isotopes are suitable for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (ie, 2H ⁾ may yield certain therapeutic advantages (eg, increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and thus in some cases is better. Isotopically labeled compounds of the invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to procedures analogous to those described in the Schemes and Examples hereinafter.

「前藥」意謂在向個體投與此類前藥時，活體內釋放根據式I之活性母體藥物之任何化合物。藉由在常規操作中或活體內，以使得改質物可活體內裂解以釋放母體化合物之方式改質式I化合物中之官能基來製備式I化合物之前藥。前藥可在單個步驟中自前藥形式轉化成活性形式，或可具有一或多種中間形式，其本身可具有活性或可為非活性。一些前藥以酶促方式活化，得到活性化合物，或在進一步化學反應時產生活性化合物之化合物。前藥包括滿足以下條件之式I化合物：式I化合物中之羥基、胺基、羧基或硫氫基鍵結至任何可活體內裂解以分別再生游離羥基、胺基或硫氫基之基團。前藥之實例包括（但不限於）式I化合物中之羥基官能基之酯（例如乙酸酯、甲酸酯及苯甲酸酯衍生物）、醯胺、胍、胺基甲酸酯（例如N,N-二甲基胺基羰基）及其類似物。前藥之其他實例包括（但不限於）活性化合物之碳酸鹽、醯脲、溶劑合物或水合物。前藥之製備、選擇及使用論述於T. Higuchi及V. Stella, 《作為新穎遞送系統之前藥（Pro-drugs as Novel Delivery Systems）》, 《A.C.S研討會系列（A.C.S. Symposium Series）》之第14卷；《前藥設計（Design of Prodrugs）》, H. Bundgaard編, Elsevier, 1985；及《藥物設計中之生物可逆載劑（Bioreversible Carriers in Drug Design）》, Edward B. Roche編, 美國藥學協會及帕加蒙出版社（American Pharmaceutical Association and Pergamon Press）, 1987中，其各自以全文引用之方式併入本文中。"Prodrug" means any compound that releases the active parent drug according to Formula I in vivo when such prodrug is administered to a subject. Prodrugs of compounds of formula I are prepared by modifying functional groups in the compounds of formula I, in routine practice or in vivo, in a manner such that the modifying substance can be cleaved in vivo to release the parent compound. A prodrug can be converted from the prodrug form to the active form in a single step, or can have one or more intermediate forms, which can themselves be active or inactive. Some prodrugs are activated enzymatically to yield the active compound, or a compound that upon further chemical reaction yields the active compound. Prodrugs include compounds of formula I where a hydroxyl, amine, carboxyl or sulfhydryl group in the compound of formula I is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amine or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in compounds of formula I (eg acetate, formate and benzoate derivatives), amides, guanidines, carbamates (eg N,N-dimethylaminocarbonyl) and its analogs. Other examples of prodrugs include, but are not limited to, carbonates, ureas, solvates, or hydrates of the active compound. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", No. 14 of the ACS Symposium Series vol; Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (American Pharmaceutical Association and Pergamon Press), 1987, each of which is incorporated herein by reference in its entirety.

如《藥物化學實踐（The Practice of Medicinal Chemistry）》, 第31-32章（Wermuth編，加拿大聖地亞哥的學術出版社（Academic Press, San Diego, CA），2001）中所描述，前藥可以在概念上分成兩種非排他性類別，生物前驅體前藥及載體前藥。通常，生物前驅體前藥為含有一或多個保護基且藉由代謝或溶劑分解轉化成活性形式之化合物，其為非活性或與相應活性藥物化合物相比活性較低。活性藥物形式及任何釋放代謝產物均應具有可接受之較低毒性。通常，活性藥物化合物之形成涉及以下一種類型之代謝過程或反應：As described in The Practice of Medicinal Chemistry, Chapters 31-32 (ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be defined in the concept It is divided into two non-exclusive categories, biological precursor prodrugs and carrier prodrugs. In general, bioprecursor prodrugs are compounds that contain one or more protecting groups and are converted by metabolism or solvolysis to an active form that is inactive or less active than the corresponding active pharmaceutical compound. The active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of an active pharmaceutical compound involves one of the following types of metabolic processes or reactions:

（1）氧化反應：氧化反應為（但不限於）所例示之反應，諸如醇、羰基及酸官能基之氧化；脂族碳之羥基化；脂環族碳原子之羥基化；芳族碳原子之氧化；碳-碳雙鍵之氧化；含氮官能基之氧化；矽、磷、砷及硫之氧化；氧化N-脫烷基化；氧化O-及S-脫烷基化；氧化脫胺化；以及其他氧化反應。(1) Oxidation reactions: Oxidation reactions are, but are not limited to, exemplified reactions such as oxidation of alcohol, carbonyl and acid functional groups; hydroxylation of aliphatic carbons; hydroxylation of alicyclic carbon atoms; aromatic carbon atoms oxidation of carbon-carbon double bonds; oxidation of nitrogen-containing functional groups; oxidation of silicon, phosphorus, arsenic and sulfur; oxidative N-dealkylation; oxidative O- and S-dealkylation; oxidative deamination chemistry; and other oxidation reactions.

（2）還原反應：還原反應為（但不限於）所例示之反應，諸如羰基官能基之還原；醇官能基及碳-碳雙鍵之還原；含氮官能基之還原；及其他還原反應。(2) Reduction Reaction: Reduction reactions are, but are not limited to, exemplified reactions such as reduction of carbonyl functional groups; reduction of alcohol functional groups and carbon-carbon double bonds; reduction of nitrogen-containing functional groups; and other reduction reactions.

（3）氧化態無改變之反應：氧化狀態無改變之反應為（但不限於）所例示之反應，諸如酯及醚之水解；碳-氮單鍵之水解***；非芳族雜環之水解***；多重鍵處之水合作用及脫水；由脫水反應產生之新的原子鍵；水解脫鹵化；鹵化氫分子之移除；及其他此類反應。(3) Reactions with no change in oxidation state: reactions with no change in oxidation state are (but not limited to) exemplified reactions, such as hydrolysis of esters and ethers; hydrolytic cleavage of carbon-nitrogen single bonds; hydrolysis of non-aromatic heterocycles cleavage; hydration and dehydration at multiple bonds; new atomic bonds resulting from dehydration reactions; hydrolytic dehalogenation; removal of hydrogen halide molecules; and other such reactions.

載體前藥為例如改良吸收及/或對作用位點之局部遞送之含有輸送部分之藥物化合物。對於此類載體前藥合乎需要地為，藥物部分與輸送部分之間的鍵為共價鍵，前藥為非活性或與藥物化合物相比活性較低，前藥及任何釋放之輸送部分為可接受地無毒。對於其中輸送部分意欲增強吸收之前藥，輸送部分之釋放通常應為快速的。在其他情況下，需要利用提供緩慢釋放之部分，例如某些聚合物或其他部分，諸如環糊精。（參見例如Cheng等人, 美國專利公開案第2004/0077595號，其以引用之方式併入本文中）。此類載體前藥通常有利於經口投與之藥物。舉例而言，載體前藥可以用於改良以下特性中之一或多種：增加之親脂性、增加之藥理學作用之持續時間、增加之位點特異性、降低之毒性及不良反應及/或藥物調配物之改良（例如穩定性、水溶性、抑制不合需要之感官或生物化學特性）。舉例而言，可藉由用親脂性羧酸進行羥基之酯化或用醇（例如脂族醇）進行羧酸基之酯化來提高親脂性。A carrier prodrug is a drug compound containing a delivery moiety, eg, to improve absorption and/or local delivery to the site of action. Desirably for such carrier prodrugs, the bond between the drug moiety and the delivery moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any released delivery moiety are available Acceptably non-toxic. For prodrugs where the delivery moiety is intended to enhance absorption, the release of the delivery moiety should generally be rapid. In other cases, it is desirable to utilize moieties that provide slow release, such as certain polymers or other moieties, such as cyclodextrins. (See, eg, Cheng et al., US Patent Publication No. 2004/0077595, which is incorporated herein by reference). Such carrier prodrugs generally facilitate oral administration of the drug therewith. For example, carrier prodrugs can be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological action, increased site specificity, decreased toxicity and adverse effects and/or drug Improvements in formulations (eg stability, water solubility, inhibition of undesirable organoleptic or biochemical properties). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids or esterification of carboxylic acid groups with alcohols, such as aliphatic alcohols.

術語「載體」亦意謂包括微球體、脂質體、微胞、奈米粒子（天然配備之奈米載體，例如胞外體）及其類似物。已知胞外體可以為高效藥物載體，且存在多種可以將藥物裝載至胞外體中之方法，包括《控制釋放雜誌（J Control Release）》, 2015年12月10日；219: 396-405中所描述之彼等技術，其內容以全文引用之方式併入本文中。The term "carrier" is also meant to include microspheres, liposomes, micelles, nanoparticles (natively equipped nanocarriers, eg, extracellular bodies), and the like. Exosomes are known to be highly effective drug carriers, and there are various methods for loading drugs into exosomes, including J Control Release, 2015 Dec 10; 219: 396-405 These techniques are described in , the contents of which are incorporated herein by reference in their entirety.

代謝物，例如活性代謝物，與如上文所描述之前藥（例如生物前驅體前藥）重疊。因此，此類代謝物為藥理學活性化合物或進一步代謝成藥理學活性化合物（其為由個體之身體內之代謝過程產生之衍生物）之化合物。其中，活性代謝物為此類藥理學活性衍生化合物。對於前藥，前藥化合物通常為非活性或與代謝產物相比活性較低。對於活性代謝物，母體化合物可為活性化合物或可為非活性前藥。Metabolites, eg, active metabolites, overlap with prodrugs (eg, bioprecursor prodrugs) as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds, which are derivatives produced by metabolic processes in the body of an individual. Among them, the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compound is generally inactive or less active than the metabolite. For active metabolites, the parent compound can be the active compound or can be an inactive prodrug.

可使用此項技術中已知之常規技術鑑別前藥及活性代謝物。參見例如Bertolini等人, 1997, 《藥物化學雜誌（J. Med. Chem.）》, 40:2011-2016；Shan等人, 1997, 《醫藥科學雜誌（J Pharm Sci）》, 86（7）:756-757；Bagshawe, 1995,《藥物衍生物研究（Drug Dev. Res.）》, 34:220-230。Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, eg, Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci, 86(7): 756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230.

「互變異構體」意謂由其中分子之一個原子之質子遷移至另一個原子之現象產生之化合物。參見Jerry March, 《高級有機化學：反應、機制及結構（Advanced Organic Chemistry: Reactions, Mechanisms and Structures）》, 第四版, John Wiley & Sons, 第69-74頁（1992）。互變異構體亦指以平衡方式存在且易於自一種異構形式轉化成另一種異構形式之兩種或兩種以上結構異構體中之一者。實例包括酮-烯醇互變異構體，諸如丙酮/丙烯-2-醇、亞胺-烯胺互變異構體及其類似物；環-鏈互變異構體，諸如葡萄糖/2,3,4,5,6-五羥基-己醛及其類似物；含有-N=C(H)-NH-環原子排列之雜芳基之互變異構形式，諸如吡唑、咪唑、苯并咪唑、***及四唑。當化合物含有例如酮或肟基團或芳族部分時，可以出現互變異構現象（tautomeric isomerism）（「互變現象（tautomerism）」）。本文中所描述之化合物可具有一或多種互變異構體且因此包括各種異構體。一般熟習此項技術者將認識到，可能存在其他互變異構環原子排列。此等化合物之所有此類異構形式明確地包括於本發明中。"Tautomer" means a compound resulting from the phenomenon in which a proton from one atom of a molecule migrates to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992). Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples include keto-enol tautomers such as acetone/propen-2-ol, imine-enamine tautomers and the like; ring-chain tautomers such as glucose/2,3,4 ,5,6-Pentahydroxy-hexanal and its analogs; tautomeric forms of heteroaryl groups containing an arrangement of -N=C(H)-NH- ring atoms, such as pyrazoles, imidazoles, benzimidazoles, tris azoles and tetrazoles. Tautomeric isomerism ("tautomerism") can occur when compounds contain, for example, ketone or oxime groups or aromatic moieties. The compounds described herein may possess one or more tautomers and thus include various isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements may exist. All such isomeric forms of these compounds are expressly included in the present invention.

「異構體」意謂具有相同分子式，但原子之鍵結性質或序列或空間中其原子之排列不同之化合物。空間中原子之排列不同之異構體稱為「立體異構體」。「立體異構體」係指以不同立體異構形式存在之化合物，舉例而言，若其具有一或多個不對稱中心或具有不對稱取代之雙鍵且因此可以個別立體異構體或混合物形式產生。立體異構體包括對映異構體及非對映異構體。彼此不為鏡像之立體異構體稱為「非對映異構體」且彼此為不可重疊之鏡像之立體異構體稱為「對映異構體」。當化合物具有不對稱中心時，舉例而言，鍵結至四個不同基團之原子，諸如碳，一對對映異構體係有可能的。對映異構體可以藉由其不對稱中心之絕對組態表徵且依據Cahn及Prelog之R-定序規則及S-定序規則描述，或藉由分子繞偏振光平面旋轉之方式描述且指定為右旋或左旋（亦即，分別為（+）或（-）-異構體）。對掌性化合物可以個別對映異構體形式或以其混合物形式存在。含有相等比例之對映異構體之混合物稱為「外消旋混合物」。作為另一實例，立體異構體包括幾何異構體，諸如雙鍵之相鄰碳上的取代基之順式或反式定向。除非另外指示，否則該描述意欲包括個別立體異構體以及混合物。用於測定一或多個立體異構中心之對掌性不同之立體異構體之立體化學及分離之方法為此項技術中熟知的（參見《高級有機化學（Advanced Organic Chemistry）》, 第6版, J. March, John Wiley and Sons, 紐約, 2007之第4章中之論述）。"Isomer" means a compound that has the same molecular formula but differs in the bonding nature or sequence or arrangement of its atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". "Stereoisomer" refers to a compound that exists in different stereoisomeric forms, for example, if it has one or more asymmetric centers or has asymmetrically substituted double bonds and thus can be individual stereoisomers or mixtures form produced. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When the compound has an asymmetric center, for example, atoms bonded to four different groups, such as carbon, a pair of enantiomeric systems is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described according to Cahn and Prelog's R-sequencing and S-sequencing rules, or by the rotation of molecules about the plane of polarized light and specified is dextrorotatory or levorotatory (ie, (+) or (-)-isomer, respectively). Parachiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". As another example, stereoisomers include geometric isomers, such as the cis or trans orientation of substituents on adjacent carbons of a double bond. Unless otherwise indicated, this description is intended to include individual stereoisomers as well as mixtures. Methods for determining the stereochemistry and separation of stereoisomers that differ in their chirality at one or more stereoisomeric centers are well known in the art (see Advanced Organic Chemistry, p. 6). ed., J. March, John Wiley and Sons, New York, 2007, Chapter 4).

「水合物」係指藉由組合水分子與溶質之分子或離子形成的複合物。「溶劑合物」係指藉由組合溶劑分子與溶質之分子或離子形成的複合物。溶劑可以為有機化合物、無機化合物或兩者之混合物。溶劑合物意謂包括水合物。溶劑之一些實例包括（但不限於）甲醇、N,N-二甲基甲醯胺、四氫呋喃、二甲亞碸及水。通常，溶合形式等效於非溶合形式且涵蓋於本發明之範疇內。"Hydrate" refers to a complex formed by combining a water molecule with a molecule or ion of a solute. "Solvate" refers to a complex formed by combining a solvent molecule with a molecule or ion of a solute. The solvent can be an organic compound, an inorganic compound or a mixture of both. Solvates are meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated form is equivalent to the non-solvated form and is encompassed within the scope of the present invention.

在作為或可為調節劑之化合物之使用、測試或篩選之情形中，術語「接觸」意謂使得化合物足夠接近特定分子、複合物、細胞、組織、生物體或潛在結合相互作用之其他指定物質及/或可以在化合物與其他指定物質之間進行化學反應。In the context of the use, testing, or screening of compounds that are or may be modulators, the term "contacting" means bringing the compound into close enough proximity to a particular molecule, complex, cell, tissue, organism, or other specified substance for potential binding interactions and/or chemical reactions can be carried out between compounds and other specified substances.

「分析」意謂實驗條件之產生及關於曝露於特定實驗條件之特定結果的資料之收集。舉例而言，可以基於其作用於可偵測底物之能力來分析酶。可以基於結合至特定目標分子或分子之能力來分析化合物。"Analysis" means the generation of experimental conditions and the collection of data regarding specific results of exposure to specific experimental conditions. For example, enzymes can be analyzed based on their ability to act on detectable substrates. Compounds can be analyzed based on the ability to bind to a particular target molecule or molecules.

如本文所使用，術語「配位體」及「調節劑」等效地用於指代改變（亦即，增加或降低）目標生物分子（例如，酶，諸如本文中所描述之酶）之活性之化合物。大體而言，配位體或調節劑將為小分子，其中「小分子」係指具有1500道爾頓（Dalton）或更少、1000道爾頓或更少、800道爾頓或更少或600道爾頓或更少之分子量之化合物。因此，「經改良之配位體」為與參考化合物相比具有更好之藥理學及/或藥物動力學特性之配位體，其中「更好」可以由特定生物學系統或治療用途之相關領域中熟習此項技術者定義。As used herein, the terms "ligand" and "modulator" are used equivalently to refer to altering (ie, increasing or decreasing) the activity of a target biomolecule (eg, an enzyme, such as those described herein) the compound. Generally, the ligand or modulator will be a small molecule, wherein "small molecule" means having 1500 Daltons or less, 1000 Daltons or less, 800 Daltons or less or Compounds with a molecular weight of 600 Daltons or less. Thus, an "improved ligand" is a ligand with better pharmacological and/or pharmacokinetic properties than a reference compound, where "better" may be related to a particular biological system or therapeutic use Those skilled in the art are familiar with this definition.

關於目標與潛在結合化合物之間的相互相用之術語「結合」指示與蛋白質之一般結合（亦即，非特異性結合）相比，潛在結合化合物與目標結合達到統計顯著程度。因此，術語「結合化合物」係指具有與目標分子之統計顯著結合之化合物。在一些實施例中，結合化合物以10 mM或更小、1,000 µM或更小、100 µM或更小、10 µM或更小、1 µM或更小、1,000 nM或更小、100 nM或更小、10 nM或更小或1 nM或更小之解離常數（K_D ）與指定目標相互作用。在結合於目標之化合物之情形下，術語「更大親和力」及「選擇性」指示化合物與參考化合物相比或與參考條件中之相同化合物相比更緊密地結合，亦即，以較低解離常數。在一些實施例中，更大親和力為至少2、3、4、5、8、10、50、100、200、400、500、1000或10,000倍更大親和力。The term "binding" as used in relation to each other between a target and a potential binding compound indicates that the potential binding compound binds to the target to a statistically significant degree compared to general binding (ie, non-specific binding) to the protein. Thus, the term "binding compound" refers to a compound that has a statistically significant binding to a target molecule. In some embodiments, the binding compound is at 10 mM or less, 1,000 µM or less, 100 µM or less, 10 µM or less, 1 µM or less, 1,000 nM or less, 100 nM or less , 10 nM or less, or 1 nM or less dissociation constant (K _D ) to interact with the designated target. In the context of a compound that binds to a target, the terms "greater affinity" and "selectivity" indicate that the compound binds more tightly, ie, with lower dissociation, than a reference compound or the same compound in a reference condition constant. In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000 or 10,000 times greater affinity.

術語「調節（modulate/modulation）」及其類似術語係指化合物增強或降低目標（諸如CD73）之功能及/或表現之能力，其中此類功能可包括轉錄調節活性及/或結合。調節可試管內或活體內進行。如本文所描述，調節包括與CD73相關聯之功能或特徵之直接或間接抑制、拮抗、部分拮抗、活化、促效或部分促效，及/或CD73之表現之直接或間接上調或下調。在另一實施例中，調節為直接的。抑制劑或拮抗劑為例如結合至、部分或完全阻斷刺激、降低、防止、抑制、延緩活化、不活化、脫敏或下調信號轉導之化合物。活化劑或促效劑為例如結合至、刺激、增加、打開、活化、促進、增強活化、活化、敏化或上調信號轉導之化合物。The terms "modulate/modulation" and similar terms refer to the ability of a compound to enhance or decrease the function and/or expression of a target, such as CD73, where such functions may include transcriptional regulatory activity and/or binding. Conditioning can be performed in vitro or in vivo. As described herein, modulation includes direct or indirect inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of functions or characteristics associated with CD73, and/or direct or indirect upregulation or downregulation of the expression of CD73. In another embodiment, the adjustment is direct. An inhibitor or antagonist is, for example, a compound that binds to, partially or completely blocks stimulation, reduces, prevents, inhibits, delays activation, inactivates, desensitizes or downregulates signal transduction. An activator or agonist is, for example, a compound that binds to, stimulates, increases, turns on, activates, promotes, enhances activation, activates, sensitizes or upregulates signal transduction.

如本文所使用，術語「治療(treat/treating)」、「療法(therapy/therapies)」及類似術語係指以有效地預防、緩解或改善疾病或病況之一或多種症狀（亦即，適應症）及/或延長所治療之個體之存活期的量投與材料，例如，如本文中所描述之任一或多種化合物。As used herein, the terms "treat/treating," "therapy/therapies," and similar terms mean to effectively prevent, alleviate, or ameliorate one or more symptoms (ie, indications) of a disease or condition ) and/or the material is administered in an amount that prolongs survival of the treated individual, eg, any one or more compounds as described herein.

如本文所使用，術語「預防（prevent/preventing/prevention）」及其語法變化形式係指用於實現以下目標之方法：部分或完全延緩或阻礙疾病、病症或病況及/或其一或多種伴隨症狀之發作或復發，或阻止個體罹患或再患病症或病況，或降低個體罹患或產生病症或病況或其一或多種伴隨症狀之風險。As used herein, the terms "prevent/preventing/prevention" and grammatical variations thereof refer to a method for achieving the goal of partially or fully delaying or hindering a disease, disorder or condition and/or one or more concomitants thereof The onset or recurrence of symptoms, or preventing an individual from developing or re-engaging in a disease or condition, or reducing the risk of an individual developing or developing a disease or condition or one or more of its accompanying symptoms.

如本文所使用，術語「個體」、「動物個體」及其類似物係指活生物體，包括（但不限於）人類及非人類脊椎動物，例如任何哺乳動物，諸如人類、其他靈長類動物、運動動物及具有商業意義之動物，諸如牛、馬、綿羊或豬，嚙齒動物或寵物，諸如犬及貓。As used herein, the terms "individual", "animal individual" and the like refer to living organisms including, but not limited to, humans and non-human vertebrates, eg, any mammal, such as humans, other primates , sport animals and animals of commercial interest such as cattle, horses, sheep or pigs, rodents or pets such as dogs and cats.

「單位劑型」係指意欲用於單次投與以治療罹患疾病或醫學病況之個體之組合物。各單位劑型通常包含本發明化合物加一或多種醫藥學上可接受之賦形劑。單位劑型之實例為個別錠劑、個別膠囊、散裝散劑、液體溶液、軟膏、乳膏、滴眼劑、栓劑、乳液或懸浮液。疾病或病況之治療可能需要單位劑型之週期性投與，例如：一天兩次或兩次以上一個單位劑型，每餐一次，每四小時或其他間隔一次，或僅每天一次。表述「口服單位劑型」指示經設計以經口服用之單位劑型。"Unit dosage form" refers to a composition intended for a single administration to treat a subject suffering from a disease or medical condition. Each unit dosage form will generally contain a compound of the present invention plus one or more pharmaceutically acceptable excipients. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions or suspensions. Treatment of a disease or condition may require periodic administration of unit dosage forms, eg, one unit dosage form twice or more a day, once with each meal, once every four hours or other intervals, or only once a day. The expression "oral unit dosage form" indicates a unit dosage form designed for oral administration.

術語「投與」係指向個體經口投與、以栓劑形式投與、表面接觸、靜脈內、腹膜內、肌肉內、病灶內、鼻內或皮下投與或移植緩慢釋放裝置（例如微滲透泵）。投與係藉由任何途徑，包括非經腸及經黏膜（例如經頰、舌下、經齶、經牙齦、經鼻、經***、經直腸或經皮）。非經腸投與包括例如靜脈內、肌肉內、小動脈內、皮內、皮下、腹膜內、室內及顱內。其他遞送模式包括（但不限於）使用脂質體調配物、靜脈內輸注、經皮貼片等。The term "administration" refers to oral administration, administration in the form of a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration or implantation of a slow release device (eg, a micro-osmotic pump) to a subject. ). Administration is by any route, including parenteral and transmucosal (eg, buccal, sublingual, palatal, transgingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

在本文中，術語「治療學上有效的」或「有效量」指示在投與時，化合物或材料或化合物或材料之量足以或有效地預防、緩解或減輕所治療之疾病、病症或醫學病況之一或多種症狀，及/或延長所治療之個體之存活期。治療有效量將視化合物、疾病、病症或病況及其嚴重性及待治療之哺乳動物之年齡、重量等而變化。一般而言，經指示，個體之滿意結果在約0.1至約10 g/kg個體體重之日劑量下獲得。在一些實施例中，日劑量在約0.10至10.0 mg/kg體重、約1.0至3.0 mg/kg體重、約3至10 mg/kg體重、約3至150 mg/kg體重、約3至100 mg/kg體重、約10至100 mg/kg體重、約10至150 mg/kg體重或約150至1000 mg/kg體重範圍內。該劑量可以便利地投與，例如以一天達四次之分次劑量或以持續釋放形式投與。As used herein, the term "therapeutically effective" or "effective amount" indicates that when administered, a compound or material or amount of compound or material is sufficient or effective to prevent, alleviate or alleviate the disease, disorder or medical condition being treated one or more symptoms, and/or prolong the survival of the treated individual. A therapeutically effective amount will vary depending on the compound, disease, disorder or condition and its severity, and the age, weight, etc., of the mammal to be treated. In general, satisfactory results for an individual are obtained at a daily dose of about 0.1 to about 10 g/kg of the individual's body weight, as indicated. In some embodiments, the daily dose is between about 0.10 to 10.0 mg/kg body weight, about 1.0 to 3.0 mg/kg body weight, about 3 to 10 mg/kg body weight, about 3 to 150 mg/kg body weight, about 3 to 100 mg /kg body weight, within the range of about 10 to 100 mg/kg body weight, about 10 to 150 mg/kg body weight, or about 150 to 1000 mg/kg body weight. The dose may be conveniently administered, eg, in divided doses up to four times a day or in sustained release form.

可以在生物化學分析（例如結合分析）或基於細胞之分析中證明化合物抑制CD73功能之能力。The ability of a compound to inhibit CD73 function can be demonstrated in biochemical assays (eg, binding assays) or cell-based assays.

如本文所使用，術語「CD73介導之疾病或病況」係指其中CD73之生物功能影響疾病或病況之發展及/或病程及/或其中CD73之調變改變發展、病程及/或症狀之疾病或病況。CD73介導之疾病或病況包括其中CD73抑制提供治療益處之疾病或病況，例如其中用CD73抑制劑（包括本文所描述之化合物）之治療向罹患疾病或病況或處於疾病或病況風險下之個體提供治療益處。CD73介導之疾病或病況意欲包括具有CD73中之功能突變之損失之癌症，或其中存在CD73之活化之癌症。CD73介導之疾病或病況亦意欲包括各種人類癌瘤，包括結腸、肺、胰腺及卵巢之人類癌瘤，以及與腫瘤新血管生成及侵襲性相關之疾病或病況。As used herein, the term "CD73-mediated disease or condition" refers to a disease in which the biological function of CD73 affects the development and/or course of the disease or condition and/or in which modulation of CD73 alters the development, course and/or symptoms or condition. CD73-mediated diseases or conditions include diseases or conditions in which inhibition of CD73 provides a therapeutic benefit, eg, in which treatment with a CD73 inhibitor, including a compound described herein, provides an individual afflicted with or at risk of a disease or condition therapeutic benefit. CD73-mediated diseases or conditions are intended to include cancers with loss of function mutations in CD73, or cancers in which activation of CD73 is present. CD73-mediated diseases or conditions are also intended to include various human cancers, including human cancers of the colon, lung, pancreas, and ovary, as well as diseases or conditions associated with tumor neovascularization and aggressiveness.

同樣，在結合至生物分子目標之化合物之情形下，術語「更大特異性」指示與可在相關結合條件下存在之另一種生物分子或多種生物分子相比，化合物以更大的程度結合至指定目標，其中與此類其他生物分子之結合產生與指定目標之結合不同的生物活性。通常，特異性參考有限的其他生物分子組，例如在CD73之情況下。在特定實施例中，更大的特異性為至少2、3、4、5、8、10、50、100、200、400、500或1000倍更大的特異性。Likewise, in the context of a compound that binds to a biomolecule target, the term "greater specificity" indicates that the compound binds to a greater degree than another biomolecule or biomolecules that may exist under the relevant binding conditions A designated target, wherein binding to such other biomolecules results in a different biological activity than binding to the designated target. Typically, specific reference is made to other groups of biomolecules that are limited, such as in the case of CD73. In certain embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500 or 1000 times greater specificity.

如本文中關於結合化合物或配位體所使用，術語「對CD73具有特異性」及具有類似含義之術語意謂與可能存在於特定樣本中之其他目標相比，特定化合物以統計學上更大的程度結合至CD73。此外，在指示除結合以外之生物活性時，術語「對CD73具有特異性」指示與其他酶相比，特定化合物具有更大的與結合CD73相關聯之生物作用，例如酶活性抑制。As used herein with respect to a binding compound or ligand, the term "specific for CD73" and terms of similar import mean that a particular compound is statistically greater than other targets that may be present in a particular sample bound to CD73. Furthermore, when indicating biological activity other than binding, the term "specific for CD73" indicates that a particular compound has a greater biological effect associated with binding to CD73 than other enzymes, eg, inhibition of enzymatic activity.

術語「第一線癌症療法」係指作為初始方案向個體投與以減少癌細胞數目之療法。第一線療法亦稱為誘導療法、初步療法及初步治療。第一線療法可以為所投與之具有一或多種藥劑之組合。關於用於某些疾病之第一線治療的當前公認的方法之概述可以見於此類疾病之NCI指南中。The term "first-line cancer therapy" refers to therapy administered to an individual as an initial regimen to reduce the number of cancer cells. First-line therapy is also known as induction therapy, primary therapy, and primary therapy. The first line therapy can be administered in combination with one or more agents. An overview of currently accepted approaches for first-line treatment of certain diseases can be found in the NCI guidelines for such diseases.

術語「第二線癌症療法」係指向不對第一線療法起反應（亦即，通常經投與第一線療法）或在緩解之後具有癌症復發之個體投與之癌症治療。在某些實施例中，可投與之第二線療法包括重複初始成功之癌症療法，其可為在「第一線癌症療法」下描述之治療中之任一者。關於用於某些疾病之第二線治療的當前公認的方法之概述描述於此類疾病之NCI指南中。The term "second-line cancer therapy" refers to the administration of cancer therapy to individuals who do not respond to first-line therapy (ie, typically administered a first-line therapy) or who have cancer recurrence after remission. In certain embodiments, a second-line therapy that can be administered includes repeating an initially successful cancer therapy, which can be any of the treatments described under "First-Line Cancer Therapy." An overview of currently accepted approaches for second-line treatment of certain diseases is described in the NCI guidelines for such diseases.

術語「難治性」係指其中個體不起反應或以其他方式對癌症療法或治療具有抗性。癌症療法可為第一線、第二線或任何後續投與之治療。在某些實施例中，難治性係指其中個體在兩次誘導嘗試之後未能實現完全緩解之病況。個體可由於癌細胞對特定療法之固有抗性而為難治性，或個體可由於在特定療法之過程期間產生之獲得性抗性而為難治性。The term "refractory" refers to those in which an individual does not respond or is otherwise resistant to a cancer therapy or treatment. Cancer therapy can be first line, second line, or any subsequent administration of treatment therewith. In certain embodiments, refractory refers to a condition in which an individual fails to achieve complete remission after two induction attempts. An individual may be refractory due to the inherent resistance of cancer cells to a particular therapy, or an individual may be refractory due to acquired resistance developed during the course of a particular therapy.

此外，如本文所使用之縮寫具有如下各別含義： ℃ 攝氏度 Ac 乙醯基 BOC 三級丁氧基羰基 DBU 1,8-二氮雜雙環[5.4.0]十一-7-烯 DCM 二氯甲烷 DEAE 二乙基胺基乙基 DMAP 二甲基胺基吡啶 DMEM 達爾伯克改良伊格爾培養基（Dulbecco's Modified Eagle's Medium） DME 二甲氧基乙烷 DMF 二甲基甲醯胺 DMSO 二甲亞碸 ESI 電噴霧電離 FBS 胎牛血清 HPLC 高效液相層析 LCMS 液相層析質譜法 [M+H+]+或(MH)+ 質量峰加氫 [M-H-]-或(MH)- 質量峰減去氫 mCPBA 間氯過氧苯甲酸 Me 甲基 MeOH 甲醇 MS 質譜 PBS 磷酸鹽緩衝生理鹽水 PTSA 對甲苯磺酸 RT 室溫 S-Phos 2-二環己基膦基-2',6'-二甲氧基聯苯基 TBAF 氟化四丁銨 TLC 薄層層析 THF 四氫呋喃 n-Bu 正丁基 N 正常 IC₅₀ 半最大（50%）抑制濃度 RP 反相 X-Phos 2-二環己基膦基-2',4',6'-三異丙基聯苯 II. 化合物 In addition, abbreviations as used herein have the following respective meanings: °C Celsius Ac Acetyl BOC tertiary butoxycarbonyl DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DEAE diethylaminoethyl DMAP dimethylaminopyridine DMEM Dulbecco's Modified Eagle's Medium DME Dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfite ESI Electrospray ionization FBS fetal bovine serum HPLC high performance liquid chromatography LCMS liquid chromatography mass spectrometry [M+H+]+ or (MH)+ Mass peak hydrogenation [MH-]- or (MH)- Mass peak minus hydrogen mCPBA m-chloroperoxybenzoic acid Me methyl MeOH methanol MS mass spectrometry PBS Phosphate-buffered saline PTSA p-Toluenesulfonic acid RT room temperature S-Phos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAF tetrabutylammonium fluoride TLC thin layer chromatography THF tetrahydrofuran n-Bu n-butyl N normal _IC50 Half-maximum (50%) inhibitory concentration RP Invert X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl II. Compounds

參考通式及特定化合物描述本文中涵蓋之化合物。此外，本文所描述之化合物可以多種不同形式或衍生物存在，其皆屬於本發明之範疇內。此等形式或衍生物包括例如互變異構體、立體異構體、外消旋混合物、區位異構體、鹽、前藥（例如羧酸酯）、溶合形式及活性代謝物。Compounds encompassed herein are described with reference to general formulae and specific compounds. In addition, the compounds described herein may exist in many different forms or derivatives, which are all within the scope of the present invention. Such forms or derivatives include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (eg, carboxylate), soluble forms, and active metabolites.

應瞭解，一些化合物可展現互變異構現象。在此類情況下，本文所提供之化學式僅明確描繪可能的互變異構形式中之一者。因此，應理解，本文所提供之化學式意欲表示所描繪之化合物之任何互變異構形式且不欲僅限於由化學式之圖式所描繪的特定互變異構形式。It will be appreciated that some compounds may exhibit tautomerism. In such cases, the chemical formulae provided herein explicitly depict only one of the possible tautomeric forms. Accordingly, it is to be understood that the chemical formulae provided herein are intended to represent any tautomeric form of the compounds depicted and are not intended to be limited to the particular tautomeric form depicted by the drawings of the chemical formulae.

類似地，根據本發明之一些化合物可以如本文所定義之立體異構體之形式存在。所有此類單一立體異構體、外消旋體及其混合物均意欲屬於本發明之範疇。除非相反地說明，否則所有此類立體異構形式包括在本文提供之式內。Similarly, some compounds according to the present invention may exist in the form of stereoisomers as defined herein. All such single stereoisomers, racemates and mixtures thereof are intended to fall within the scope of this invention. Unless stated to the contrary, all such stereoisomeric forms are included in the formulae provided herein.

在一些實施例中，本發明之對掌性化合物呈含有至少80%單一異構體（60%對映異構過量（「e.e.」）或非對映異構過量（「d.e.」）），或至少85%（70% e.e.或d.e.）、90%（80% e.e.或d.e.）、95%（90% e.e.或d.e.）、97.5%（95% e.e.或d.e.）或99%（98% e.e.或d.e.）之形式。如熟習此項技術者一般所瞭解，具有一個對掌性中心之光學純化合物為基本上由兩種可能對映異構體中之一者組成的化合物（亦即為對映異構性純），且具有一個以上對掌性中心之光學純化合物為非對映異構性純與對映異構純之化合物。在一些實施例中，化合物以光學純形式存在。In some embodiments, the parachiral compounds of the invention contain at least 80% single isomer (60% enantiomeric excess ("ee") or diastereomeric excess ("de")), or At least 85% (70% ee or de), 90% (80% ee or de), 95% (90% ee or de), 97.5% (95% ee or de) or 99% (98% ee or de) the form of. As is generally understood by those skilled in the art, an optically pure compound having one antichiral center is one that consists essentially of one of two possible enantiomers (ie, is enantiomerically pure) , and optically pure compounds with more than one chiral center are diastereomerically pure and enantiomerically pure compounds. In some embodiments, the compounds exist in optically pure form.

對於其中合成涉及在雙鍵，尤其碳-碳雙鍵處添加單一基團之化合物，添加可在雙鍵連接之原子中之任一者處進行。對於此類化合物，本發明包括兩種此類區位異構體。For compounds in which the synthesis involves the addition of a single group at a double bond, especially a carbon-carbon double bond, the addition can take place at any of the atoms to which the double bond is attached. For such compounds, the present invention includes both such regioisomers.

除本文所描述之本發明之化學式及化合物以外，本發明亦包括前藥（通常醫藥學上可接受之前藥）、活性代謝衍生物（活性代謝物）及其醫藥學上可接受之鹽。In addition to the formulae and compounds of the invention described herein, the invention also includes prodrugs (usually pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites) and pharmaceutically acceptable salts thereof.

除非相反地說明，否則本文中化合物之說明書包括此類化合物之醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物。Unless stated to the contrary, descriptions of compounds herein include pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or deuterated analogs of such compounds.

在一些實施例中，本發明之化合物與酸或鹼複合，包括鹼加成鹽，諸如銨、二乙胺、乙醇胺、乙二胺、二乙醇胺、三級丁胺、哌

、葡甲胺；酸加成鹽，諸如乙酸鹽、乙醯基水楊酸鹽、苯磺酸鹽、樟腦磺酸鹽、檸檬酸鹽、甲酸鹽、反丁烯二酸鹽、戊二酸鹽、鹽酸鹽、順丁烯二酸鹽、甲磺酸鹽、硝酸鹽、草酸鹽、磷酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽及甲苯磺酸鹽；以及胺基酸，諸如丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、麩醯胺酸、麩胺酸、甘胺酸、組胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、***酸、脯胺酸、絲胺酸、蘇胺酸、色胺酸、酪胺酸或纈胺酸。在一些情況下，藉由另一加工（諸如藉由噴霧乾燥、機械化學方法（諸如滾筒壓實）或微波照射與酸或鹼混合之母體化合物）促進複合物之非晶形式。此類方法亦可包括添加離子性及/或非離子性聚合物系統，包括（但不限於）乙酸羥基丙基甲基纖維素丁二酸酯（HPMCAS）及甲基丙烯酸共聚物（例如Eudragit® L100-55），其進一步使複合物之非晶形性質穩定。此類非晶形複合物提供若干優點。舉例而言，相對於游離鹼降低熔融溫度有助於其他處理（諸如熱熔擠壓），以進一步改良化合物之生物醫藥特性。此外，非晶型複合物容易破碎，從而提供改良之壓縮以將固體裝載於膠囊或錠劑形式中。化合物實施例 In some embodiments, the compounds of the present invention are complexed with acids or bases, including base addition salts, such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, tertiary butylamine, piperazine

, meglumine; acid addition salts such as acetate, acetylsalicylate, benzenesulfonate, camphorsulfonate, citrate, formate, fumarate, glutaric acid salts, hydrochlorides, maleates, mesylates, nitrates, oxalates, phosphates, succinates, sulfates, tartrates, thiocyanates and tosylates; and Amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, histidine, isoleucine, white Amino acid, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. In some cases, the amorphous form of the complex is promoted by another processing, such as by spray drying, mechanochemical methods (such as roller compaction), or microwave irradiation of the parent compound mixed with acid or base. Such methods may also include the addition of ionic and/or non-ionic polymer systems including, but not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers such as Eudragit® L100-55), which further stabilizes the amorphous nature of the complex. Such amorphous composites offer several advantages. For example, lowering the melt temperature relative to the free base facilitates other processing, such as hot melt extrusion, to further improve the biomedical properties of the compound. In addition, the amorphous complexes are easily broken, thereby providing improved compression for loading solids in capsule or lozenge form. Compound Examples

本發明之實施例 1 係關於式I之化合物：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中：A 係5-6員芳族環或4-7員含氮雜環烷基，其中A經0-3個R⁴ 取代，其限制條件為當環A為4-7員含氮雜環烷基時，則式I之嗒

酮部分連接至A之氮原子；E 係苯基或5或6員雜芳基，其中E經0-3個Q及0-1個R¹¹ 取代，其限制條件為當E為5或6員雜芳基時，O不連接至E之雜原子；L 不存在，為-C(O)N(H)-、C₀ -C₃ 伸烷基、-N(H)-或-O-；G 為以下基團中之一者： (a)          經0-4個T¹ 及0-1個T² 取代之環烷基； (b)         經0-4個T¹ 及0-1個T² 取代之環烯基； (c)          經0-4個T¹ 及0-1個T² 取代之橋接碳環； (d)         碳環螺環，其含有兩個藉由一個共同螺碳原子連接之環烷基，其中碳環螺環係經0-4個T¹ 及0-1個T² 取代； (e)          含有兩個具有至少一個雜原子之環狀基團之雜環螺環，其中該兩個環狀基團由一個共同螺碳原子連接，其中該雜環螺環經0-3個T⁵ 、0-1個T⁶ 取代； (f)           經0-4個T¹ 及0-1個T⁴ 取代之苯基； (g)         經0-4個T⁵ 及0-1個T⁶ 取代之雜環烷基； (h)         經0-4個T⁵ 及0-1個T⁶ 取代之雜環烯基； (i)           經0-4個T⁵ 及0-1個T⁶ 取代之橋接雜環；或 (j)           經0-3個T⁵ 及0-1個T³ 取代之雜芳基； 各Q 獨立地為鹵素、CN或視情況經1-3個鹵素取代之烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之烷基、視情況經1-3個R^b 取代之烯基、視情況經1-3個R^b 取代之炔基、CN、氰烷基、視情況經1-3個R^b 取代之烷氧基或視情況經1-3個R^b 取代之烷氧基烷基；T² 係-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -C(O)R¹⁰ 、-(CH₂ )_0-3 -C(O)H、-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ 、視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基；T³ 係-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -環烷基、-(CH₂ )_0-3 -環烯基、-(CH₂ )_0-3 -雜環烷基、-(CH₂ )_0-3 -雜環烯基、視情況經4-氯嗒

-3-酮-5-基取代之-O-雜環烷基，或-(CH₂ )_0-3 -橋接碳環，其中-(CH₂ )_0-3 -環烷基、-(CH₂ )_0-3 -環烯基、-(CH₂ )_0-3 -雜環烷基、-(CH₂ )_0-3 -雜環烯基，或-(CH₂ )_0-3 -橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不可以連接至T³ 之氧原子或氮原子；T⁴ 係-(CH₂ )_0-3 C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ ，或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之烷基、視情況經1-3個R^b 取代之烯基、視情況經1-3個R^b 取代之炔基、CN、氰烷基、視情況經1-3個R^b 取代之烷氧基，或視情況經1-3個R^b 取代之烷氧基烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之烷氧基；T⁶ 係-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -C(O)R¹⁰ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氮原子或氧原子。R^a 為H或烷基；R^b 為鹵素、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ；R¹ 為H、烷氧基烷基、經0-4個Z² 取代之烯基或經0-4個Z² 取代之C₂ -C₆ 烷基；R² 為H、鹵素、烷基、烯基、烷氧基、鹵烷基、CF₃ 或CN；R³ 為H、鹵素、烷基、CN或鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之烷基；R⁷ 係視情況經1-4個Z⁴ 取代之烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基；R⁸ 係H、視情況經1-4個Z⁴ 取代之烷基、視情況經1-4個Z⁴ 取代之烯基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基、視情況1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基，或經0-5個T¹ 取代之橋接碳環； 各R⁹ 獨立地為H或視情況經1-4個Z⁴ 取代之烷基；R¹⁰ 係經0-4個Z⁴ 取代之烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基；R¹¹ 為NH₂ ；Z¹ 為氰烷基、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為C(O)OR⁹ ； 各Z² 獨立地為羥基、鹵素、NH₂ 或CN，其限制條件為不超過1個Z² 可以為NH₂ ； 各Z³ 獨立地為烷基、鹵素、鹵烷基、羥基、羥烷基、烷氧基、烷氧基烷基或CN； 各Z⁴ 獨立地為羥基、鹵素、烷氧基或CN；且 各Z⁵ 獨立地為烷基、鹵烷基、羥基、羥烷基、鹵素、烷氧基、烷氧基烷基、CN或氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、烷氧基或CN。實施例 1 之子實施例 Example 1 of the present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein: A is a 5-6 membered aromatic ring or a 4-7 membered nitrogen-containing heterocycloalkane group, wherein ^A is substituted with 0-3 R4, with the limitation that when ring A is a 4-7 membered nitrogen-containing heterocycloalkyl, then the formula I

The ketone moiety is attached to the nitrogen atom of A; E is phenyl or 5- or ⁶ -membered heteroaryl, wherein E is substituted with 0-3 Q and 0-1 R, with the proviso that when E is 5- or 6-membered In the case of heteroaryl, O is not attached to the heteroatom of E; L is absent and is -C(O)N(H)-, Co _{- C3alkylene} , -N(H)- or -O-; G is one of the following groups: (a) cycloalkyl substituted with 0-4 T ¹ and 0-1 T ² ; (b) 0-4 T ¹ and 0-1 T ² substituted cycloalkenyl; (c) bridged carbocycles substituted with 0-4 T ¹ and 0-1 T ² ; (d) carbocyclic spiro rings, which contain two spiro rings connected by a common spiro carbon atom Cycloalkyl, wherein the carbocyclic spiro ring system is substituted with 0-4 T ¹ and 0-1 T ² ; (e) Heterocyclic spiro rings containing two cyclic groups with at least one heteroatom, wherein the Two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring is substituted by 0-3 T ⁵ , 0-1 T ⁶ ; (f) by 0-4 T ¹ and 0-1 phenyl substituted with T ⁴ ; (g) heterocycloalkyl substituted with 0-4 T ⁵ and 0-1 T ⁶ ; (h) substituted with 0-4 T ⁵ and 0-1 T ⁶ (i) a bridged heterocycle substituted with 0-4 T ⁵ and 0-1 T ⁶ ; or (j) a heterocycle substituted with 0-3 T ⁵ and 0-1 T ³ Aryl; each Q is independently halogen, CN or alkyl optionally substituted with 1-3 halogens; each T ¹ is independently halogen, hydroxy, optionally alkyl substituted with 1-3 R ^b , optionally Alkenyl optionally substituted with 1-3 R ^b , alkynyl optionally substituted with 1-3 R ^b , CN, cyanoalkyl, alkoxy optionally substituted with 1-3 R ^b or optionally Alkoxyalkyl substituted with 1-3 R ^b ; T ² is -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ - R ⁷ , -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _{0- 3} -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)N(R ⁸ )R ⁹ ,-(CH ₂ ) _0-3 -C(O)OR ⁹ , -(CH ₂ ) _0-3 -C(O)R ¹⁰ , -(CH ₂ ) _0-3 -C(O)H, -(CH ₂ ) _{0 -3} -N(R ⁹ )C(O)R ¹⁰ , optionally -(CH ₂ ) _0-3 cycloalkyl substituted with 1-4 Z ³ , optionally substituted with 1-3 Z ⁵ - (CH ₂ ) _0-3 -phenyl, or optionally -(CH ₂ ) _0-3 heteroaryl substituted with 1-3 Z ⁵ ; T ³ is -(CH ₂ ) _0-3 -C(O )N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)OR ⁹ , -(CH ₂ ) _0-3 -Cycloalkyl, -( _CH2 ) _0-3 -cycloalkenyl, -( _CH2 ) _0-3 -heterocycloalkyl, -( _CH2 ) _0-3 -heterocycloalkenyl, optionally via 4 - Chloro

-O-heterocycloalkyl substituted with -3-keto-5-yl, or -(CH ₂ ) _0-3 -bridged carbocycle, wherein -(CH ₂ ) _0-3 -cycloalkyl, -(CH ₂ ) _0-3 -cycloalkenyl, -( _CH2 ) _0-3 -heterocycloalkyl, -( _CH2 ) _0-3 -heterocycloalkenyl, or -( _CH2 ) _0-3 -bridged carbocycle Each is optionally substituted with 1-3 Z ⁵ and 0-1 Z ¹ , with the limitation that when T ³ is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of T ³ ; T ⁴ System -(CH ₂ ) _0-3 C(O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 - N(R ⁹ )C(O)N(R ⁸ )R ⁹ , or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, alkyl optionally substituted with 1-3 R ^b , optionally Alkenyl optionally substituted with 1-3 R ^b , alkynyl optionally substituted with 1-3 R ^b , CN, cyanoalkyl, alkoxy optionally substituted with 1-3 R ^b , or optionally substituted with 1-3 R b Case alkoxyalkyl substituted with 1-3 R ^b , with the proviso that when T ⁵ is attached to a heteroatom of G, T ⁵ cannot be halogen, hydroxy, CN or optionally 1-3 R ^b Substituted alkoxy; T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ -R ⁷ , -(CH ₂ ) _{0 -3} -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-3 -N(R ⁹ )C( O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _{0 -3} -C(O)OR ⁹ , -(CH ₂ ) _0-3 -C(O)R ¹⁰ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ¹⁰ , -N( H)C(H)C=O, optionally substituted with 1-4 Z ³ -(CH ₂ ) _0-3 cycloalkyl, optionally substituted with 1-4 Z ³ -(CH ₂ ) _{0 -2} Heterocycloalkyl, as the case may be Substituted with 1-3 Z ⁵ -(CH ₂ ) _0-3 heteroaryl, or 4-chloroda

-3-keto-5-yl with the limitation that when ^T6 is attached to a heteroatom of G, G cannot be attached to a nitrogen or oxygen atom of ^T6 . R ^a is H or alkyl; R ^b is halogen, CN, CF ₃ or hydroxyl, with the limitation that no more than 1 R ^b can be CF ₃ ; R ¹ is H, alkoxyalkyl, through 0-4 Z ² substituted alkenyl or C ₂ -C ₆ alkyl substituted with 0-4 Z ² ; R ² _is H, halogen, alkyl, alkenyl, alkoxy, haloalkyl, CF or CN R ³ is H, halogen, alkyl, CN or haloalkyl; each R ⁴ is independently halogen, CN or alkyl optionally substituted with 1-3 halogens; R ⁷ is optionally substituted with 1-4 halogens Z ⁴ substituted alkyl, optionally -C ₀ -C ₃ alkyl-cycloalkyl substituted with 1-4 Z ³ , -C ₀ -C ₃ alkyl optionally substituted with 1-4 Z ³ -Phenyl, -C ₀ -C ₃ alkyl-heteroaryl optionally substituted with 1-3 Z ⁵ , or -C ₀ -C ₃ alkyl-heteroaryl optionally substituted with 1-3 Z ⁵ Cycloalkyl; R ⁸ is H, optionally substituted with 1-4 Z ⁴ alkyl, optionally substituted with 1-4 Z ⁴ alkenyl, optionally substituted with 1-4 Z ³ -C ₀ -C3 alkyl _- cycloalkyl, optionally _{-C0 -} C3 alkyl-phenyl substituted with 1-4 Z3, optionally _-C0 ^- C substituted with ^1-3 Z5 ₃ alkyl-heteroaryl, optionally -C ₀ -C ₃ alkyl-heterocycloalkyl substituted with 1-3 Z ⁵ , or bridged carbocycle substituted with 0-5 T ¹ ; each R ⁹ is independent R is H or alkyl substituted by 1-4 Z ⁴ as appropriate; R ¹⁰ is alkyl substituted by 0-4 Z ⁴ , -C ₀ -C ₃ substituted by 1-4 Z ³ as appropriate Alkyl-cycloalkyl, optionally substituted with 1-4 Z ³ -C ₀ -C ₃ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₃ alkyl- Heteroaryl, or -C ₀ -C ₃ alkyl-heterocycloalkyl substituted with 1-3 Z ⁵ as appropriate; R ¹¹ is NH ₂ ; Z ¹ is cyanoalkyl, -(CH ₂ ) _{0- 2} -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , with the restriction that when Z ¹ is attached to a heteroatom, then Z ¹ is not C (O)OR ⁹ ; each Z ² is independently hydroxyl, halogen, NH ₂ or CN, with the limitation that no more than one Z ² can be NH ₂ ; each Z ³ is independently alkyl, halogen, haloalkyl , hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl or CN; each ^Z is independently hydroxy, halogen, alkoxy or CN; and each ^Z is independently alkyl, haloalkyl, hydroxy , hydroxyalkyl, halogen, alkoxy, alkoxyalkyl, CN or ^cyanoalkyl , with the proviso that when Z is attached to a heteroatom, then ^Z is not halogen, hydroxy, alkoxy or CN . Sub-Example of Example 1

實施例 1 （ a ） 係關於實施例1，其中A為5-6員芳族環，其中A經0-3個R⁴ 取代。 Example 1 ( a ) relates to Example 1, wherein A is a 5-6 membered aromatic ring, wherein ^A is substituted with 0-3 R4.

實施例 1 （ b ） 係關於實施例1，其中A為4-7員含氮雜環烷基，其限制條件為式I之嗒

酮部分連接至A之氮原子。 Embodiment 1 ( b ) relates to embodiment 1, wherein A is a 4-7 membered nitrogen-containing heterocycloalkyl, subject to the restriction that A is of formula I

The ketone moiety is attached to the nitrogen atom of A.

實施例 1 （ c ） 係關於實施例1、1（a）或1（b）中之任一項，其中E係經0-3個Q及0-1個R¹¹ 取代之苯基。 Embodiment 1 ( c ) relates to any one of Embodiments 1, 1(a) or ¹ (b), wherein E is phenyl substituted with 0-3 Q and 0-1 R11.

實施例 1 （ d ） 係關於實施例1、1（a）或1（b）中之任一者，其中E為5或6員雜芳基，其中E經0-3個Q及0-1個R¹¹ 取代，其限制條件為O不連接至E之雜原子。 Embodiment 1 ( d ) relates to any one of Embodiments 1, 1(a), or 1(b), wherein E is a 5- or 6-membered heteroaryl, wherein E is separated by 0-3 Q and 0-1 R ¹¹ substitutions with the proviso that O is not attached to the heteroatom of E.

實施例 1 （ e ） 係關於實施例1、1（a）、1（b）、1（c）或1（d）中之任一者，其中L不存在， Embodiment 1 ( e ) relates to any of Embodiments 1, 1(a), 1(b), 1(c), or 1(d), wherein L is absent,

實施例 1 （ f ） 係關於實施例1、1（a）、1（b）、1（c）或1（d）中之任一者，其中L為-C(O)N(H)-。 Embodiment 1 ( f ) relates to any one of Embodiments 1, 1(a), 1(b), 1(c), or 1(d), wherein L is -C(O)N(H)- .

實施例 1 （ g ） 係關於實施例1、1（a）、1（b）、1（c）或1（d）中之任一者，其中L為C₀ -C₃ 伸烷基。 Embodiment 1 ( g ) relates to any of Embodiments 1, 1(a), 1(b), 1(c), or 1(d ₎ , wherein L is a Co _- C3 alkylene.

實施例 1 （ h ） 係關於實施例1、1（a）、1（b）、1（c）或1（d）中之任一者，其中L為-N(H)-。 Embodiment 1 ( h ) relates to any of Embodiments 1, 1(a), 1(b), 1(c), or 1(d), wherein L is -N(H)-.

實施例 1 （ i ） 係關於實施例1、1（a）、1（b）、1（c）或1（d）中之任一者，其中L為-O-。 Embodiment 1 ( i ) relates to any of Embodiments 1, 1(a), 1(b), 1(c), or 1(d), wherein L is -O-.

實施例 1 （ j ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T¹ 及0-1個T² 取代之環烷基。 Example 1 ( j ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is cycloalkyl substituted with 0-4 T ¹ and 0-1 T ² .

實施例 1 （ k ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T¹ 及0-1個T² 取代之環烯基。 Example 1 ( k ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is cycloalkenyl substituted with 0-4 T ¹ and 0-1 T ² .

實施例 1 （ l ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T¹ 及0-1個T² 取代之橋接碳環。 Example 1 ( l ) is related to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is a bridged carbocycle substituted with 0-4 T ¹ and 0-1 T ² .

實施例 1 （ m ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G為含有兩個藉由一個常見螺碳原子連接之環烷基的碳環螺環，其中該碳環螺環係經0-4個T¹ 及0-1個T² 取代。 Example 1 ( m ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is a carbocyclic spiro ring containing two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic spiro ring is connected by 0-4 T ¹ and 0-1 T ² substitutions.

實施例 1 （ n ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G為含有具有至少一個雜原子之兩個環狀基團之雜環螺環，其中兩個環狀基團藉由一個共同螺碳原子連接，其中雜環螺環係經0-3個T⁵ 、0-1個T⁶ 取代。 Example 1 ( n ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is a heterocyclic spiro ring containing two cyclic groups with at least one heteroatom, wherein the two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted by 0-3 T ⁵ and 0-1 T ⁶ .

實施例 1 （ o ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T¹ 及0-1個T⁴ 取代之苯基。 Example 1 ( o ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is phenyl substituted with 0-4 T ¹ and 0-1 T ⁴ .

實施例 1 （ p ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T⁵ 及0-1個T⁶ 取代之雜環烷基。 Example 1 ( p ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is heterocycloalkyl substituted with 0-4 T ⁵ and 0-1 T ⁶ .

實施例 1 （ q ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T⁵ 及0-1個T⁶ 取代之雜環烯基。 Example 1 ( q ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is heterocycloalkenyl substituted with 0-4 T ⁵ and 0-1 T ⁶ .

實施例 1 （ r ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-4個T⁵ 及0-1個T⁶ 取代之橋接雜環。 Example 1 ( r ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h) ) or any of 1(i), wherein G is a bridged heterocycle substituted with 0-4 T ⁵ and 0-1 T ⁶ .

實施例 1 （ s ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中G係經0-3個T⁵ 及0-1個T³ 取代之雜芳基。 Example 1 ( s ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein G is heteroaryl substituted with 0-3 T ⁵ and 0-1 T ³ .

實施例 1 （ t ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 。 Example 1 ( t ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) SO ₂ -R ⁷ .

實施例 1 （ u ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -SO₂ -R⁷ 。 Example 1 ( u ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h) ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T ² is -(CH ₂ ) _0-3 -SO ₂ -R ⁷ .

實施例 1 （ v ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Example 1 ( v ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) SO ₂ N(R ⁸ )R ⁹ .

實施例 1 （ w ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Example 1 ( w ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)N(R ⁸ )R ⁹ .

實施例 1 （ x ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 。 Example 1 ( x ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)R ⁸ .

實施例 1 （ y ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ 。 Example 1 ( y ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)OR ⁹ .

實施例 1 （ z ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁸ )R⁹ 。 Example 1 ( z ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁸ ) ^R9 .

實施例 1 （ aa ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 。 Example 1 ( aa ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T ² is -(CH ₂ ) _0-3 -C(O)N (R ⁸ )R ⁹ .

實施例 1 （ ab ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -C(O)OR⁹ 。 Example 1 ( ab ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), where T ² is -(CH ₂ ) _0-3 -C(O)OR ⁹ .

實施例 1 （ ac ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -C(O)R¹⁰ 。 Example 1 ( ac ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T ² is -(CH ₂ ) _0-3 -C(O)R ¹⁰ .

實施例 1 （ ad ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -C(O)H。 Example 1 ( ad ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T ² is -(CH ₂ ) _0-3 -C(O)H .

實施例 1 （ ae ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ 。 Example 1 ( ae ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), or 1(m), wherein T ² is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)R ¹⁰ .

實施例 1 （ af ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基。 Example 1 ( af ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T2 is -( ^{CH )} substituted by 1-4 Z3 as appropriate ₂ ) _0-3 cycloalkyl.

實施例 1 （ ag ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -苯基。 Example 1 ( ag ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T2 is -( ^{CH )} substituted by 1-3 Z5 as appropriate ₂ ) _0-3 -phenyl.

實施例 1 （ ah ） 係關於如實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -苯基。 Example 1 ( ah ) relates to examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1( Any of h), 1(i), 1(j), 1(k), 1(l) or ¹ (m), wherein T2 is ^- ( substituted by 1-3 Z5 as appropriate CH ₂ ) _0-3 -phenyl.

實施例 1 （ ai ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）或1（m）中之任一者，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基。 Example 1 ( ai ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l) or 1(m), wherein T2 is -( ^{CH )} substituted by 1-3 Z5 as appropriate ₂ ) _0-3 heteroaryl.

實施例 1 （ aj ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 。 Example 1 ( aj ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _0-3 -C(O)N(R ⁸ )R ⁹ .

實施例 1 （ ak ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為-(CH₂ )_0-3 -N(R⁸ )R⁹ ，其限制條件為當T³ 連接至G之雜原子時,T³ 不可以為-N(R⁸ )R⁹ 。 Example 1 ( ak ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , with the proviso that when T ³ is attached to the heterogeneity of G When atomic, T ³ cannot be -N(R ⁸ )R ⁹ .

實施例 1 （ al ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為-(CH₂ )_0-3 -C(O)OR⁹ 。 Example 1 ( al ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _0-3 -C(O)OR ⁹ .

實施例 1 （ am ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-3 -環烷基。 Example 1 ( am ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _0-3 -cycloalkane substituted with 1-3 Z ⁵ and 0-1 Z ¹ as appropriate base.

實施例 1 （ an ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-3 -雜環烷基，其限制條件為當T³ 連接至G之雜原子時，G不可以連接至T³ 之氮原子或氧原子。 Example 1 ( an ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _{0-3 -heterocycle} substituted with 1-3 Z ⁵ and 0-1 Z ¹ as appropriate Alkyl, with the proviso that when T3 is attached to a heteroatom ^of G, G may not be attached to a nitrogen or oxygen atom ^of T3.

實施例 1 （ ao ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-雜環烷基，其限制條件為-O-雜環烷基不連接至G之雜原子。 Example 1 ( ao ) relates to examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), or 1(s), wherein T3 is optionally via ⁴ -chlorine

-O-heterocycloalkyl substituted with -3-keto-5-yl, with the proviso that -O-heterocycloalkyl is not attached to a G heteroatom.

實施例 1 （ ap ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（s）中之任一者，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-3 -橋接碳環。 Example 1 ( ap ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(s), wherein T ³ is -(CH ₂ ) _0-3 - bridging carbon substituted with 1-3 Z ⁵ and 0-1 Z ¹ as appropriate ring.

實施例 1 （ aq ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）或1（i）中之任一者，其中T⁴ 為-(CH₂ )_0-3 C(O)OR⁹ 。 Example 1 ( aq ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ) or any of 1(i), wherein T ⁴ is -(CH ₂ ) _0-3 C(O)OR ⁹ .

實施例 1 （ ar ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（o）中之任一者，其中T⁴ 為-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 。 Example 1 ( ar ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(o), wherein T ⁴ is —(CH ₂ ) _0-3 —N(R ⁹ )SO ₂ —R ⁷ .

實施例 1(as) 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（o）中之任一者，其中T⁴ 為-(CH₂ )_0-3 -SO₂ -R⁷ 。 Example 1(as) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(o), wherein T ⁴ is -(CH ₂ ) _0-3 -SO ₂ -R ⁷ .

實施例 1 （ at ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（o）中之任一者，其中T⁴ 為-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 。 Example 1 ( at ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(o), wherein T ⁴ is -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ )R ⁹ .

實施例 1 （ au ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（o）中之任一者，其中T⁴ 為-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Example 1 ( au ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(o), wherein T ⁴ is -(CH ₂ ) _0-3 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

實施例 1 （ av ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）或1（o）中之任一者，其中T⁴ 為N(R^a )₂ 。 Example 1 ( av ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i) or 1(o), wherein T ⁴ is N(R ^a ) ₂ .

實施例 1 （ aw ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁹ )SO₂ -R⁷ 。 Example 1 ( aw ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) SO ₂ -R ⁷ with the restriction that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁹ )SO ₂ -R ⁷ .

實施例 1 （ ax ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -SO₂ -R⁷ 。 Example 1 ( ax ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -SO ₂ -R ⁷ .

實施例 1 （ ay ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 。 Example 1 ( ay ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ ) ^R9 .

實施例 1 （ az ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Example 1 ( az ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) SO ₂ N(R ⁸ )R ⁹ with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

實施例 1 （ ba ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Example 1 ( ba ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)N(R ⁸ )R ⁹ with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

實施例 1 （ bb ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為N(R⁹ )C(O)R⁸ 。 Example 1 ( bb ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)R ⁸ with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be N(R ⁹ )C(O)R ⁸ .

實施例 1 （ bc ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁹ )C(O)OR⁹ 。 Example 1 ( bc ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)OR ⁹ with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁹ )C(O)OR ⁹ .

實施例 1 （ bd ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁸ )R⁹ 。 Example 1 ( bd ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁸ ) R ⁹ , with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁸ )R ⁹ .

實施例1（be）係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -C(O)-N(R⁸ )R⁹ 。Example 1(be) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -C(O)- N(R ⁸ )R ⁹ .

實施例 1 （ bf ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -C(O)OR⁹ 。 Example 1 ( bf ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -C(O)OR ⁹ .

實施例 1 （ bg ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -C(O)R¹⁰ 。 Example 1 ( bg ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -C(O)R ¹⁰ .

實施例 1 （ bh ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，則T⁶ 不可以為-N(R⁹ )C(O)OR¹⁰ 。 Example 1 ( bh ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or 1(r), wherein T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ ) C(O)R ¹⁰ with the limitation that when T ⁶ is attached to a heteroatom of G, then T ⁶ cannot be -N(R ⁹ )C(O)OR ¹⁰ .

實施例 1 （ bi ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Example 1 ( bi ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q), or ¹ (r), wherein T is -N(H)C(H)C=O, which The limitation is that ^T6 is not attached to a G heteroatom.

實施例 1 （ bj ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基。 Example 1 ( bj ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein ^T6 is -(CH ⁾ optionally substituted by 1-4 Z3 ₂ ) _0-3 cycloalkyl.

實施例 1 （ bk ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-2 雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氮原子或氧原子。 Example 1 ( bk ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein ^T6 is -(CH ⁾ optionally substituted by 1-4 Z3 ₂ ) _0-2 heterocycloalkyl, with the limitation that when ^T6 is attached to a heteroatom of G, G cannot be attached to a nitrogen or oxygen atom of ^T6 .

實施例 1 （ bl ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（n）、1（p）、1（q）或1（r）中之任一者，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氮原子或氧原子。 Example 1 ( bl ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(n), 1(p), 1(q) or 1(r), wherein ^T6 is ^- (CH) optionally substituted by 1-3 Z5 ₂ ) _0-3 heteroaryl, with the limitation that when ^T6 is attached to a heteroatom of G, G cannot be attached to a nitrogen or oxygen atom of ^T6 .

實施例 1 （ bm ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）、1（m）、1（n）、1（o）、1（p）、1（q）、1（r）、1（s）、1（t）、1（u）、1（v）、1（w）、1（x）、1（y）、1（z）、1（aa）、1（ab）、1（ac）、1（ad）、1（ae）、1（af）、1（ag）、1（ah）、1（ai）、1（aj）、1（ak）、1（al）、1（am）、1（an）、1（ao）、1（ap）、1（aq）、1（ar）、1（as）、1（at）、1（au）、1（av）、1（aw）、1（ax）、1（ay）、1（az）、1（ba）、1（bb）、1（bc）、1（bd）、1（be）、1（bf）、1（bg）、1（bh）、1（bi）、1（bj）、（bk）或1（bl）中之任一者，其中R¹ 為氫。 Example 1 ( bm ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r ), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab ), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1(aj), 1(ak), 1(al ), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av) ), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf) ), 1(bg), 1(bh), 1(bi), 1(bj), (bk) or 1(bl), wherein R ¹ is hydrogen.

實施例 1 （ bn ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）、1（m）、1（n）、1（o）、1（p）、1（q）、1（r）、1（s）、1（t）、1（u）、1（v）、1（w）、1（x）、1（y）、1（z）、1（aa）、1（ab）、1（ac）、1（ad）、1（ae）、1（af）、1（ag）、1（ah）、1（ai）、1（aj）、1（ak）、1（al）、1（am）、1（an）、1（ao）、1（ap）、1（aq）、1（ar）、1（as）、1（at）、1（au）、1（av）、1（aw）、1（ax）、1（ay）、1（az）、1（ba）、1（bb）、1（bc）、1（bd）、1（be）、1（bf）、1（bg）、1（bh）、1（bi）、1（bj）、（bk）或1（b1）中之任一者，其中R¹ 係經0-4個羥基取代之C₂ -C₆ 烷基。 Example 1 ( bn ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r ), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab ), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1(aj), 1(ak), 1(al ), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av) ), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf) ), 1(bg), 1(bh), 1(bi), 1(bj), (bk) or 1(b1), wherein R ¹ is C ₂ substituted with 0-4 hydroxy groups -C ₆ alkyl.

實施例 1 （ bo ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）、1（m）、1（n）、1（o）、1（p）、1（q）、1（r）、1（s）、1（t）、1（u）、1（v）、1（w）、1（x）、1（y）、1（z）、1（aa）、1（ab）、1（ac）、1（ad）、1（ae）、1（af）、1（ag）、1（ah）、1（ai）、1（aj）、1（ak）、1（al）、1（am）、1（an）、1（ao）、1（ap）、1（aq）、1（ar）、1（as）、1（at）、1（au）、1（av）、1（aw）、1（ax）、1（ay）、1（az）、1（ba）、1（bb）、1（bc）、1（bd）、1（be）、1（bf）、1（bg）、1（bh）、1（bi）、1（bj）、（bk）、1（bl）、1（bm）或1（bn）中之任一者，其中R² 為鹵素。 Example 1 ( bo ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r ), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab ), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1(aj), 1(ak), 1(al ), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av) ), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf) ), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm), or ¹ (bn), where R is halogen.

實施例 1 （ bp ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）、1（m）、1（n）、1（o）、1（p）、1（q）、1（r）、1（s）、1（t）、1（u）、1（v）、1（w）、1（x）、1（y）、1（z）、1（aa）、1（ab）、1（ac）、1（ad）、1（ae）、1（af）、1（ag）、1（ah）、1（ai）、1（aj）、1（ak）、1（al）、1（am）、1（an）、1（ao）、1（ap）、1（aq）、1（ar）、1（as）、1（at）、1（au）、1（av）、1（aw）、1（ax）、1（ay）、1（az）、1（ba）、1（bb）、1（bc）、1（bd）、1（be）、1（bf）、1（bg）、1（bh）、1（bi）、1（bj）、（bk）、1（bl）、1（bm）或1（bn）中之任一者，其中R² 為CN。 Example 1 ( bp ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r ), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab ), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1(aj), 1(ak), 1(al ), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av) ), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf) ), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm), or ¹ (bn), where R is EN.

實施例 1 （ bq ） 係關於實施例1、1（a）、1（b）、1（c）、1（d）、1（e）、1（f）、1（g）、1（h）、1（i）、1（j）、1（k）、1（l）、1（m）、1（n）、1（o）、1（p）、1（q）、1（r）、1（s）、1（t）、1（u）、1（v）、1（w）、1（x）、1（y）、1（z）、1（aa）、1（ab）、1（ac）、1（ad）、1（ae）、1（af）、1（ag）、1（ah）、1（ai）、1（aj）、1（ak）、1（al）、1（am）、1（an）、1（ao）、1（ap）、1（aq）、1（ar）、1（as）、1（at）、1（au）、1（av）、1（aw）、1（ax）、1（ay）、1（az）、1（ba）、1（bb）、1（bc）、1（bd）、1（be）、1（bf）、1（bg）、1（bh）、1（bi）、1（bj）、（bk）、1（bl）、1（bm）、1（bn）、1（bo）或1（bp）中之任一者，其中R³ 為H。 Example 1 ( bq ) relates to Examples 1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h ), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r ), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x), 1(y), 1(z), 1(aa), 1(ab ), 1(ac), 1(ad), 1(ae), 1(af), 1(ag), 1(ah), 1(ai), 1(aj), 1(ak), 1(al ), 1(am), 1(an), 1(ao), 1(ap), 1(aq), 1(ar), 1(as), 1(at), 1(au), 1(av) ), 1(aw), 1(ax), 1(ay), 1(az), 1(ba), 1(bb), 1(bc), 1(bd), 1(be), 1(bf) ), 1(bg), 1(bh), 1(bi), 1(bj), (bk), 1(bl), 1(bm), 1(bn), 1(bo) or 1(bp) Any of wherein ^R3 is H.

本發明之實施例 2 係關於如實施例1、1之化合物，其中環A為吖呾、吡咯啶、哌啶、咪唑、噻唑或吡唑基。實施例 2 之子實施例 Embodiment 2 of the present invention relates to compounds as in Embodiments 1 and 1, wherein Ring A is acridine, pyrrolidine, piperidine, imidazole, thiazole or pyrazolyl. Sub-Example of Example 2

本發明之實施例 2 （ a ） 係關於如實施例2之化合物，其中環A為吖呾。 Embodiment 2 ( a ) of the present invention relates to the compound of Embodiment 2, wherein Ring A is acridine.

本發明之實施例 2 （ b ） 係關於如實施例2之化合物，其中環A為吡咯啶。 Embodiment 2 ( b ) of the present invention relates to the compound of Embodiment 2, wherein Ring A is pyrrolidine.

本發明之實施例 2 （ c ） 係關於如實施例2之化合物，其中環A為哌啶。 Embodiment 2 ( c ) of the present invention relates to the compound of embodiment 2, wherein ring A is piperidine.

本發明之實施例 2 （ d ） 係關於如實施例2之化合物，其中環A為咪唑。 Embodiment 2 ( d ) of the present invention relates to the compound as embodiment 2, wherein ring A is imidazole.

本發明之實施例 2 （ e ） 係關於如實施例2之化合物，其中環A為噻唑。 Embodiment 2 ( e ) of the present invention relates to the compound of Embodiment 2, wherein Ring A is thiazole.

本發明之實施例 2 （ f ） 係關於如實施例2之化合物，其中環A為吖呾。 Embodiment 2 ( f ) of the present invention relates to a compound as in Embodiment 2, wherein Ring A is acridine.

本發明之實施例 2 （ g ） 係關於如實施例2之化合物，其中環A為吡唑基。 Embodiment 2 ( g ) of the present invention relates to the compound of Embodiment 2, wherein Ring A is pyrazolyl.

本發明之實施例 3係關於如實施例1之化合物，其具有式II：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中L 不存在，為-N(H)-或-O-；且m 為0-2。 Example 3 of the present invention relates to a compound as Example 1 having formula II:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein L is absent, -N(H)- or -O-; and m is 0 -2.

本發明之實施例 4 係關於如實施例1之化合物，其具有式IIIa或IIIb：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中：E 為苯基或6員雜芳基，其中E經0-2個Q取代，其限制條件為當E為6員雜芳基時，O不連接至E之雜原子；G 為以下基團中之一者： (a)      經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (b)      經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (c)      經0-3個T¹ 及0-1個T² 取代之5-9員橋接碳環； (d)      5-9員碳環螺環，其含有兩個由一個共同螺碳原子連接之環烷基，其中該碳環螺環係經0-3個T¹ 及0-1個T² 取代； (e)      6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-3個T⁵ 、0-1個T⁶ 取代； (f)       經0-3個T¹ 及0-1個T⁴ 取代之苯基； (g)      經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基； (h)      經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基； (i)       經0-3個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (j)       經0-3個T⁵ 及0-1個T³ 取代之5-6員雜芳基； 各Q獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₃ 烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₆ 烷基、視情況經1-3個R^b 取代之C₂ -C₅ 烯基、視情況經1-3個R^b 取代之C₂ -C₅ 炔基、CN、C₁ -C₆ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基C₁ -C₆ 烷基；T² 係-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)R¹⁰ 、-(CH₂ )_0-2 -C(O)H、-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ 、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -5-6員雜芳基；T³ 係-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基、視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基，或-(CH₂ )_0-2 -5-9員橋接碳環，其中-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基或-(CH₂ )_0-2 -5-9員橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不連接至T³ 之氧原子或氮原子；T⁴ 係-(CH₂ )_0-2 C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₆ 烷基、視情況經1-3個R^b 取代之C₂ -C₆ 烯基、視情況經1-3個R^b 取代之C₂ -C₆ 炔基、CN、C₁ -C₆ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基C₁ -C₆ 烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基；T⁶ 係-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)R¹⁰ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -5-6員雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -5-6員雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至T⁶ 之氧原子或氮原子；R^a 係H或C₁ -C₆ 烷基；R^b 為鹵素、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ； 各R¹ 為氫、C₁ -C₆ 烷氧基C₁ -C₆ 烷基、經1-4個Z² 取代之C₂ -C₆ 烯基或經1-4個Z² 取代之C₂ -C₆ 烷基；R² 為H、鹵素、C₁ -C₆ 烷基、C₂ -C₆ 烯基、C₁ -C₆ 烷氧基、C₁ -C₆ 鹵烷基、CF₃ 或CN；R³ 為H、鹵素、C₁ -C₆ 烷基、CN或C₁ -C₆ 鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₃ 烷基；R⁷ 為視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基，視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基；R⁸ 係H、視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z⁴ 取代之C₂ -C₆ 烯基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基，或經0-4個T¹ 取代之5-9員橋接碳環； 各R⁹ 獨立地為H或視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基；R¹⁰ 係經0-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基；R¹¹ 為NH₂ ；Z¹ 為C₁ -C₆ 氰烷基、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為-C(O)OR； 各Z² 獨立地為羥基、鹵素、CN； 各Z³ 獨立地為C₁ -C₆ 烷基、鹵素、C₁ -C₆ 鹵烷基、羥基、C₁ -C₆ 羥烷基、C₁ -C₆ 烷氧基或CN； 各Z⁴ 獨立地為羥基、鹵素、C₁ -C₆ 烷氧基或CN；且 各Z⁵ 獨立地為C₁ -C₆ 烷基、C₁ -C₆ 鹵烷基、羥基、C₁ -C₆ 羥烷基、鹵素、C₁ -C₆ 烷氧基、CN或C₁ -C₆ 氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、C₁ -C₆ 烷氧基或CN。實施例 4 之子實施例 Embodiment 4 of the present invention relates to a compound as in embodiment 1 having formula Ilia or IIIb:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein: E is phenyl or 6-membered heteroaryl, wherein E is through 0-2 Q Substituted with the proviso that when E is a 6-membered heteroaryl, O is not attached to a heteroatom of E; G is one of the following groups: (a) via 0-3 T and ^0-1 C ₃ -C ₆ cycloalkyl substituted with T ² ; (b) C 3 -C 6 cycloalkenyl substituted with 0-3 T ¹ and 0-1 T ² ; (c) C ₃ -C ₆ cycloalkenyl substituted with 0-3 T s ¹ and 0-1 T substituted 5-9 membered bridged carbocyclic rings; (d) 5-9 membered carbocyclic spiro rings containing ^two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic ring The spiro ring system is substituted with 0-3 T ¹ and 0-1 T ² ; (e) a 6-9 membered heterocyclic spiro ring containing two cyclic groups with at least one heteroatom, wherein the two The cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted with 0-3 T ⁵ , 0-1 T ⁶ ; (f) with 0-3 T ¹ and 0-1 phenyl substituted with T ⁴ ; (g) 4-6 membered heterocycloalkyl substituted with 0-3 T ⁵ and 0-1 T ⁶ ; (h) 0-3 T ⁵ and 0-1 4-6 membered heterocycloalkenyl substituted with T ⁶ ; (i) 5-9 membered bridged heterocycle substituted with 0-3 T ⁵ and 0-1 T ⁶ ; or (j) with 0-3 T 6 5-6 membered heteroaryl substituted with T ⁵ and 0-1 T ³ ; each Q is independently halogen, CN or C ₁ -C ₃ alkyl substituted with 1-3 halogen as the case may be; each T ¹ is independently is halogen, hydroxy, optionally C ₁ -C ₆ alkyl substituted with 1-3 R ^b , optionally C ₂ -C ₅ alkenyl substituted with 1-3 R ^b , optionally 1-3 C ₂ -C ₅ alkynyl substituted with 1 R ^b , CN, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ alkoxy substituted with 1-3 R ^b as appropriate, or optionally 1-C 6 alkoxy substituted with 1-3 R b C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted with 3 R ^b ; T ² is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ N(R ⁸ ) R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)R ¹⁰ , -(CH ₂ ) _0-2 -C(O)H, -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ , as appropriate -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl substituted with 1-4 Z ³ , optionally -(CH ₂ ) _0-2 -phenyl substituted with 1-3 Z ⁵ , or -(CH ₂ ) 0-2-5-6 membered heteroaryl _optionally substituted by 1-3 Z ⁵ ; T ³ is -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C ₃ -C ₆ ring Alkyl, -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl, optionally via 4-chloro

-O-5-6-membered heterocycloalkyl substituted by -3-keto-5-yl, or -(CH ₂ ) _0-2 -5-9-membered bridged carbocycle, wherein -(CH ₂ ) _0-2 - C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-2 -5-6 membered heterocycloalkyl or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycle each optionally via 1-3 Z ⁵ and 0-1 Z ¹ substitutions, with the limitation that when T ³ is attached to the heteroatom of G, G is not attached to the oxygen or nitrogen atom of T ³ ; T ⁴ is -(CH ₂ ) _{0- 2} C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ , - (CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O ) N(R ⁸ )R ⁹ or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, optionally C ₁ -C ₆ alkyl substituted with 1-3 R ^b , optionally 1- C ₂ -C ₆ alkenyl substituted with 3 R ^b , C ₂ -C ₆ alkynyl optionally substituted with 1-3 R ^b , CN, C ₁ -C ₆ cyanoalkyl, optionally 1-3 C ₁ -C ₆ alkoxy substituted with R ^b , or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted with 1-3 R ^b as the case may be, with the limitation that when T ⁵ is attached To the heteroatom of G, T ⁵ cannot be halogen, hydroxyl, CN or C ₁ -C ₆ alkoxy substituted by 1-3 R ^b as appropriate; T ⁶ is -(CH ₂ ) _0-2 -N (R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _{0 -2} -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _{0 -2} -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ ) R ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 - C(O)R ¹⁰ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ , -N(H)C(H)C=O, via 1-4 Z ³ as appropriate replaced by -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl substituted by 1-4 Z ³ , optionally by 1-3 -(CH ₂ ) _0-3-5-6 -membered heteroaryl substituted by Z ⁵ , or 4-chloroda

-3-keto- ⁵ -yl, with the proviso that when T is attached to a heteroatom of G, G is not attached to an oxygen or nitrogen atom of T; ^R is H or C ₁ -C ⁶ alkyl _; R ^b is halogen, CN, CF ₃ or hydroxyl, with the limitation that no more than one R ^b can be CF ₃ ; each R ¹ is hydrogen, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, via 1-4 Z ² substituted C ₂ -C ₆ alkenyl or 1-4 Z ² substituted C ₂ -C ₆ alkyl; R ² is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, CF ₃ or CN; R ³ is H, halogen, C ₁ -C ₆ alkyl, CN or C ₁ -C ₆ haloalkyl; each R ⁴ is independently halogen, CN or C ₁ -C ₃ alkyl optionally substituted with 1-3 halogens; R ⁷ is C ₁ - optionally substituted with 1-4 Z ⁴ C ₆ alkyl, optionally -C ₀ -C ₂ alkyl-C ₃ -C ₆ cycloalkyl substituted with 1-4 Z ³ , optionally -C ₀ -C substituted with 1-4 Z ³ ₂ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heteroaryl, or optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heterocycloalkyl; R ⁸ is H, optionally C ₁ -C ₆ alkyl substituted with 1-4 Z ⁴ , optionally substituted with 1-4 Z ⁴ C ₂ -C ₆ alkenyl, optionally -C ₀ -C ₂ alkyl-C ₃ -C ₆ cycloalkyl substituted with 1-4 Z ³ , optionally -C substituted with 1-4 Z ³ ₀ -C ₂ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heteroaryl, optionally substituted with 1-3 Z ⁵ - C ₀ -C ₂ alkyl-5-6 membered heterocycloalkyl, or a 5-9 membered bridged carbocycle substituted with 0-4 T ¹ ; each R ⁹ is independently H or optionally through 1-4 Z ⁴ substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl substituted with 0-4 Z ⁴ , optionally -C ₀ -C ₂ alkane substituted with 1-4 Z ³ base-C ₃ -C ₆ cycloalkyl, optionally -C ₀ -C ₂ alkyl-phenyl substituted with 1-4 Z ³ , -C ₀ -C optionally substituted with 1-3 Z ⁵ ₂ -alkyl-5-6-membered heteroaryl, or -C ₀ -C ₂ -alkyl-5-6-membered heterocycloalkyl substituted by 1-3 Z ⁵ as appropriate; R ¹¹ is NH ₂ ; Z ¹ is C ₁ -C ₆ cyanoalkyl, -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , which limits The condition is that when Z ¹ is attached to the heterogen Z ¹ is not -C(O)OR; each Z ² is independently hydroxyl, halogen, CN; each Z ³ is independently C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkane group, hydroxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, or CN; each Z ⁴ is independently hydroxy, halogen, C ₁ -C ₆ alkoxy, or CN; and each Z ⁵ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, C ₁ -C ₆ hydroxyalkyl, halogen, C ₁ -C ₆ alkoxy, CN or C ₁ -C ₆ cyanoalkane radical, with the proviso that when Z ⁵ is attached to a heteroatom, then Z ⁵ is not halogen, hydroxy, C ₁ -C ₆ alkoxy, or CN. Sub-Example of Example 4

本發明之實施例 4 （ a ） 係關於如具有式IIIa之實施例4之化合物或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物。 Embodiment 4 ( a ) of the present invention relates to a compound such as Embodiment 4 of formula IIIa or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof.

本發明之實施例 4 （ b ） 係關於如具有式IIIb之實施例4之化合物或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物。 Embodiment 4 ( b ) of the present invention relates to a compound such as Embodiment 4 of formula IIIb or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof.

本發明之實施例 4 （ c ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基。 Embodiment 4 ( c ) of the present invention relates to a compound as embodiment 4, 4(a) or ⁴ (b), wherein G is C3- substituted with _0-3 T1 and ^0-1 T2 C ₆ cycloalkyl.

本發明之實施例 4 （ d ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基。 Embodiment 4 ( d ) of the present invention relates to a compound as in embodiment 4, 4(a) or ⁴ (b), wherein G is C3- substituted with _0-3 T1 and ^0-1 T2 C ₆ cycloalkenyl.

本發明之實施例 4 （ e ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T¹ 及0-1個T² 取代之5-9員橋接碳環。 Embodiment 4 ( e ) of the present invention relates to a compound as embodiment 4, 4(a) or ⁴ (b), wherein G is 5-9 substituted with 0-3 T1 and ^0-1 T2 Member bridges the carbon ring.

本發明之實施例 4 （ f ） 係關於如實施例4、4（a）或4（b）之化合物，其中G為含有兩個環烷基之5-9員碳環螺環，該等環烷基由一個共同螺碳原子連接，其中碳環螺環係經0-3個T¹ 及0-1個T² 取代。 Embodiment 4 ( f ) of the present invention relates to a compound as in Embodiment 4, 4(a) or 4(b), wherein G is a 5-9 membered carbocyclic spiro ring containing two cycloalkyl groups, and these rings The alkyl groups are linked by a common spiro carbon atom, wherein the carbocyclic spiro ring system is substituted with 0-3 T ¹ and 0-1 T ² .

本發明之實施例 4 （ g ） 係關於如實施例4、4（a）或4（b）之化合物，其中G為含有兩個具有至少一個雜原子之環狀基團的6-9員雜環螺環，其中兩個環狀基團由一個共同螺碳原子連接，其中雜環螺環係經0-3個T⁵ 、0-1個T⁶ 取代。 Embodiment 4 ( g ) of the present invention relates to a compound as in Embodiment 4, 4(a) or 4(b), wherein G is a 6-9 membered heterocyclic group containing two cyclic groups having at least one heteroatom Cyclic spiro rings, wherein the two cyclic groups are joined by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted with 0-3 ^T5 , 0-1 ^T6 .

本發明之實施例 4 （ h ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T¹ 及0-1個T⁴ 取代之苯基。 Embodiment 4 ( h ) of the present invention relates to a compound as embodiment 4, 4(a) or ⁴ (b), wherein G is phenyl substituted with 0-3 T1 and ^0-1 T4.

本發明之實施例 4 （ i ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基。 Embodiment 4 ( i ) of the present invention relates to a compound as embodiment 4, 4(a) or ⁴ (b), wherein G is ^4-6 substituted with 0-3 T5 and 0-1 T6 membered heterocycloalkyl.

本發明之實施例 4 （ j ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基。 Embodiment 4 ( j ) of the present invention relates to a compound as embodiment 4, 4(a) or ⁴ (b), wherein G is ^4-6 substituted with 0-3 T5 and 0-1 T6 Member heterocycloalkenyl.

本發明之實施例 4 （ k ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環。 Embodiment 4 ( k ) of the present invention relates to a compound as embodiment 4, 4(a) or 4(b), wherein G is ^5-9 substituted with 0-3 T5 and 0-1 ^T6 Member bridged heterocycle.

本發明之實施例 4 （ l ） 係關於如實施例4、4（a）或4（b）之化合物，其中G係經0-3個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 4 ( l ) of the present invention relates to a compound as embodiment 4, 4(a) or 4(b), wherein G is ^5-6 substituted with ^0-3 T5 and 0-1 T3 Member heteroaryl.

本發明之實施例 4 （ m ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 4 ( m ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 4 （ n ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -SO₂ -R⁷ 。 Embodiment 4 ( n ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -SO ₂ -R ⁷ .

本發明之實施例 4 （ o ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 。 Embodiment 4 ( o ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 4 （ p ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 4 ( p ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 4 （ q ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 4 ( q ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 4 （ r ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 。 Example 4 ( r ) of the present invention relates to a compound such as Example 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 4 （ s ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ 。 Embodiment 4 ( s ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ .

本發明之實施例 4 （ t ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁸ )R⁹ 。 Embodiment 4 ( t ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ .

本發明之實施例 4 （ u ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 4 ( u ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ .

本發明之實施例 4 （ v ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 4 ( v ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -C(O)OR ⁹ .

本發明之實施例 4 （ w ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -C(O)R¹⁰ 。 Embodiment 4 ( w ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -C(O)R ¹⁰ .

本發明之實施例 4 （ x ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -C(O)H。 Embodiment 4 ( x ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -( _CH2 ) _0-2 -C(O)H.

本發明之實施例 4 （ y ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ 。 Embodiment 4 ( y ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 4 （ z ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為視情況經1-4個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基。 Embodiment 4 ( z ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl optionally substituted with 1-4 Z ³ .

本發明之實施例 4 （ aa ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -苯基。 Embodiment 4 ( aa ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -( _CH2 ) _0-2 ^- phenyl optionally substituted with 1-3 Z5.

本發明之實施例 4 （ ab ） 係關於如實施例4、4（a）、4（b）、4（c）、4（d）、4（e）或4（f）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -5-6員雜芳基。 Embodiment 4 ( ab ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(c), 4(d), 4(e) or 4(f), wherein T ² is -(CH ₂ ) _0-2-5-6 membered heteroaryl optionally substituted with 1-3 Z ⁵ .

本發明之實施例 4 （ ac ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 4 ( ac ) of the present invention relates to a compound as embodiment 4, 4(a), 4(b) or ⁴ (l), wherein T3 is -( _CH2 ) _0-2 -C(O) N(R ⁸ )R ⁹ .

本發明之實施例 4 （ ad ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為T³ 連接至G之雜原子，G不連接至N(R⁸ )R⁹ 。 Embodiment 4 ( ad ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or ⁴ (l), wherein T3 is -( _CH2 ) _0-2 -N( ^R8 ) R ⁹ , with the proviso that T ³ is attached to a heteroatom of G, which is not attached to N(R ⁸ )R ⁹ .

本發明之實施例 4 （ ae ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 4 ( ae ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or 4(l), wherein T ³ is -(CH ₂ ) _0-2 -C(O) OR ⁹ .

本發明之實施例 4 （ af ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 4 ( af ) of the present invention relates to a compound as embodiment 4, 4(a), 4(b) or ⁴ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl substituted with Z ¹ .

本發明之實施例 4 （ ag ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T³ 不連接至G之雜原子時。 Embodiment 4 ( ag ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or ⁴ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl substituted with Z ¹ , with the limitation that when T ³ is not attached to a G heteroatom.

本發明之實施例 4 （ ah ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基。 Embodiment 4 ( ah ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or 4(l), wherein T3 is optionally via ⁴ -chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl.

本發明之實施例 4 （ ai ） 係關於如實施例4、4（a）、4（b）或4（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-9員橋接碳環。 Embodiment 4 ( ai ) of the present invention relates to a compound as embodiment 4, 4(a), 4(b) or ⁴ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 Z ¹ is substituted with -(CH ₂ ) _0-2-5-9 member bridged carbocycle.

本發明之實施例 4 （ aj ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 C(O)OR⁹ 。 Embodiment 4 ( aj ) of the present invention relates to a compound as embodiment 4, 4(a), 4(b) or ⁴ (h), wherein T4 is -( _CH2 ) _0-2C (O)OR ⁹ .

本發明之實施例 4 （ ak ）係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 。 Embodiment 4 ( ak ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or 4(h), wherein T ⁴ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 4 （ al ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 4 ( a1 ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or ⁴ (h), wherein T4 is -( _CH2 ) _0-2 -N( ^R9 )SO ₂ -R ⁷ .

本發明之實施例 4 （ am ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 -SO₂ -R⁷ 。 Embodiment 4 ( am ) of the present invention relates to a compound as embodiment 4, 4(a), 4(b) or ⁴ (h), wherein T4 is -( _CH2 ) _0-2 -SO2 _- R ⁷ .

本發明之實施例 4 （ an ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 。 Embodiment 4 ( an ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or 4(h), wherein T ⁴ is -(CH ₂ ) _0-2 -SO ₂ N( R ⁸ )R ⁹ .

本發明之實施例 4 （ ao ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 4 ( ao ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b) or 4(h), wherein T ⁴ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 4 （ ap ） 係關於如實施例4、4（a）、4（b）或4（h）之化合物，其中T⁴ 為N(R^a )₂ 。 Embodiment 4 ( ap ) of the present invention relates to a compound as in Embodiment 4, 4(a), 4(b) or ⁴ (h), wherein T4 is N( ^Ra ) ₂ .

本發明之實施例 4 （ aq ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ -R⁷ 。 Embodiment 4 ( aq ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ - ^R7 .

本發明之實施例 4 （ ar ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -SO₂ -R⁷ 。 Embodiment 4 ( ar ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -SO ₂ -R ⁷ .

本發明之實施例 4 （ as ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -SO₂ N(R⁸ )R。 Embodiment 4 ( as ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R.

本發明之實施例 4 （ at ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 4 ( at ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 4 （ au ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 4 ( au ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N( R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 4 （ av ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R⁸ 。 Embodiment 4 ( av ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O)R ⁸ .

本發明之實施例 4 （ aw ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)OR⁹ 。 Embodiment 4 ( aw ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O) ^OR9 .

本發明之實施例 4 （ ax ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 4 ( ax ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 4 （ ay ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ 。 Embodiment 4 ( ay ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ .

本發明之實施例 4 （ az ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 4 ( az ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -C(O)OR ⁹ .

本發明之實施例 4 （ ba ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -C(O)R¹⁰ 。 Embodiment 4 ( ba ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -C(O)R ¹⁰ .

本發明之實施例 4 （ bb ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R¹⁰ 。 Embodiment 4 ( bb ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O)R ¹⁰ .

本發明之實施例 4 （ bc ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Embodiment 4 ( bc ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -N(H)C(H)C=O, with the proviso that ^T6 is not attached to a G heteroatom.

本發明之實施例 4 （ bd ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 4 ( bd ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl optionally substituted with 1-4 Z ³ .

本發明之實施例 4 （ be ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜環烷基之氧原子或氮原子。 Embodiment 4 ( be ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl optionally substituted with 1-4 Z ³ , with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to Oxygen atom or nitrogen atom of 5-6 membered heterocycloalkyl.

本發明之實施例 4 （ bf ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -5-6員雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之氧原子或氮原子。 Embodiment 4 ( bf ) of the present invention relates to a compound such as Embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ is -(CH ₂ ) _0-3-5-6 membered heteroaryl optionally substituted with 1-3 Z ⁵ , with the proviso that when T ⁶ is attached to the heteroatom of G, G is not attached to 5 - Oxygen atom or nitrogen atom of a 6-membered heteroaryl group.

本發明之實施例 4 （ bg ） 係關於如實施例4、4（a）、4（b）、4（g）、4（i）、4（j）或4（k）之化合物，其中T⁶ 為或4-氯嗒

-3-酮-5-基。 Embodiment 4 ( bg ) of the present invention relates to a compound such as embodiment 4, 4(a), 4(b), 4(g), 4(i), 4(j) or 4(k), wherein T ⁶ for or 4-chlorota

-3-keto-5-yl.

實施例 4 （ bh ） 係關於實施例4、4（a）、4（b）、4（c）、4（d）、4（e）、4（f）、4（g）、4（h）、4（i）、4（j）、4（k）、4（l）、4（m）、4（n）、4（o）、4（p）、4（q）、4（r）、4（s）、4（t）、4（u）、4（v）、4（w）、4（x）、4（y）、4（z）、4（aa）、4（ab）、4（ac）、4（ad）、4（ae）、4（af）、4（ag）、4（ah）、4（ai）、4（aj）、4（ak）、4（al）、4（am）、4（an）、4（ao）、4（ap）、4（aq）、4（ar）、4（as）、4（at）、4（au）、4（av）、4（aw）、4（ax）、4（ay）、4（az）、4（ba）、4（bb）、4（bc）、4（bd）、（be）、4（bf）或4（bg）中之任一者，其中R¹ 為氫。 Example 4 ( bh ) relates to Examples 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h ), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r ), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab ), 4(ac), 4(ad), 4(ae), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al ), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av) ), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf) or any of 4(bg), wherein R ¹ is hydrogen.

實施例 4 （ bi ） 係關於實施例4、4（a）、4（b）、4（c）、4（d）、4（e）、4（f）、4（g）、4（h）、4（i）、4（j）、4（k）、4（l）、4（m）、4（n）、4（o）、4（p）、4（q）、4（r）、4（s）、4（t）、4（u）、4（v）、4（w）、4（x）、4（y）、4（z）、4（aa）、4（ab）、4（ac）、4（ad）、4（ae）、4（af）、4（ag）、4（ah）、4（ai）、4（aj）、4（ak）、4（al）、4（am）、4（an）、4（ao）、4（ap）、4（aq）、4（ar）、4（as）、4（at）、4（au）、4（av）、4（aw）、4（ax）、4（ay）、4（az）、4（ba）、4（bb）、4（bc）、4（bd）、（be）、4（bf）或4（bg）中之任一者，其中R¹ 係經0-4個羥基取代之C₂ -C₆ 烷基。 Example 4 ( bi ) relates to Examples 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h ), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r ), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab ), 4(ac), 4(ad), 4(ae), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al ), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av) ), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf) or any of 4(bg), wherein R ¹ is C ₂ -C ₆ alkyl substituted with 0-4 hydroxy groups.

實施例 4 （ bj ） 係關於實施例4、4（a）、4（b）、4（c）、4（d）、4（e）、4（f）、4（g）、4（h）、4（i）、4（j）、4（k）、4（l）、4（m）、4（n）、4（o）、4（p）、4（q）、4（r）、4（s）、4（t）、4（u）、4（v）、4（w）、4（x）、4（y）、4（z）、4（aa）、4（ab）、4（ac）、4（ad）、4（ae）、4（af）、4（ag）、4（ah）、4（ai）、4（aj）、4（ak）、4（al）、4（am）、4（an）、4（ao）、4（ap）、4（aq）、4（ar）、4（as）、4（at）、4（au）、4（av）、4（aw）、4（ax）、4（ay）、4（az）、4（ba）、4（bb）、4（bc）、4（bd）、（be）、4（bf）或4（bg）中之任一者，其中R² 為鹵素。 Example 4 ( bj ) relates to Examples 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h ), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r ), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab ), 4(ac), 4(ad), 4(ae), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al ), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av) ), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf) or any of 4(bg), wherein R ² is halogen.

實施例 4 （ bk ） 係關於實施例4、4（a）、4（b）、4（c）、4（d）、4（e）、4（f）、4（g）、4（h）、4（i）、4（j）、4（k）、4（l）、4（m）、4（n）、4（o）、4（p）、4（q）、4（r）、4（s）、4（t）、4（u）、4（v）、4（w）、4（x）、4（y）、4（z）、4（aa）、4（ab）、4（ac）、4（ad）、4（ae）、4（af）、4（ag）、4（ah）、4（ai）、4（aj）、4（ak）、4（al）、4（am）、4（an）、4（ao）、4（ap）、4（aq）、4（ar）、4（as）、4（at）、4（au）、4（av）、4（aw）、4（ax）、4（ay）、4（az）、4（ba）、4（bb）、4（bc）、4（bd）、（be）、4（bf）或4（bg）中之任一者，其中R² 為CN。 Example 4 ( bk ) relates to Examples 4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h ), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r ), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab ), 4(ac), 4(ad), 4(ae), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al ), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av) ), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf) or any of 4(bg), wherein R ² is CN.

實施例 4 （ bl ） 係關於實施例14、4（a）、4（b）、4（c）、4（d）、4（e）、4（f）、4（g）、4（h）、4（i）、4（j）、4（k）、4（l）、4（m）、4（n）、4（o）、4（p）、4（q）、4（r）、4（s）、4（t）、4（u）、4（v）、4（w）、4（x）、4（y）、4（z）、4（aa）、4（ab）、4（ac）、4（ad）、4（ae）、4（af）、4（ag）、4（ah）、4（ai）、4（aj）、4（ak）、4（al）、4（am）、4（an）、4（ao）、4（ap）、4（aq）、4（ar）、4（as）、4（at）、4（au）、4（av）、4（aw）、4（ax）、4（ay）、4（az）、4（ba）、4（bb）、4（bc）、4（bd）、（be）、4（bf）或4（bg）中之任一者，其中R³ 為H。 Example 4 ( bl ) relates to Examples 14, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h ), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), 4(o), 4(p), 4(q), 4(r ), 4(s), 4(t), 4(u), 4(v), 4(w), 4(x), 4(y), 4(z), 4(aa), 4(ab ), 4(ac), 4(ad), 4(ae), 4(af), 4(ag), 4(ah), 4(ai), 4(aj), 4(ak), 4(al ), 4(am), 4(an), 4(ao), 4(ap), 4(aq), 4(ar), 4(as), 4(at), 4(au), 4(av) ), 4(aw), 4(ax), 4(ay), 4(az), 4(ba), 4(bb), 4(bc), 4(bd), (be), 4(bf) or any of 4(bg), wherein ^R3 is H.

本發明之實施例 5 係關於如前述實施例中任一項之化合物，其中：E 為苯基或6員雜芳基，其中E經0-1個Q取代，其限制條件為當E為6員雜芳基時，O不連接至E之雜原子；G 為以下基團中之一者： (a)      經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (b)      經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (c)      經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環； (d)      5-9員碳環螺環，其含有兩個由一個共同螺碳原子連接之環烷基，其中該碳環螺環係經0-2個T¹ 及0-1個T² 取代； (e)      6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代； (f)       經0-2個T¹ 及0-1個T⁴ 取代之苯基； (g)      經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基； (h)      經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基； (i)       經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (j)       經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基； 各Q 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₄ 烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₄ 烷基、視情況經1-3個R^b 取代之C₂ -C₄ 烯基、視情況經1-3個R^b 取代之C₂ -C₄ 炔基、CN、C₁ -C₄ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基C₁ -C₄ 烷基；T² 係-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)R¹⁰ 、-(CH₂ )_0-1 -C(O)H、-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 、視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基；T³ 係-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基、視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基，或-(CH₂ )_0-2 -5-9員橋接碳環，其中-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-1 -5-6員雜環烷基或-(CH₂ )_0-2 -5-9員橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不連接至T³ 之氧原子或氮原子； T⁴ 係-(CH₂ )_0-1 C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₄ 烷基、視情況經1-3個R^b 取代之C₂ -C₄ 烯基、視情況經1-3個R^b 取代之C₂ -C₄ 炔基、CN、C₁ -C₄ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基C₁ -C₄ 烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基；T⁶ 係-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)R¹⁰ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至T⁶ 之氧原子或氮原子；R^a 為H或C₁ -C₄ 烷基；R^b 為F、Cl、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ；R¹ 為H、C₁ -C₄ 烷氧基C₁ -C₄ 烷基、經1-3個Z² 取代之C₂ -C₄ 烯基或經1-3個Z² 取代之C₂ -C₄ 烷基；R² 為H、鹵素、C₁ -C₄ 烷基、C₂ -C₄ 烯基、C₁ -C₄ 烷氧基、C₁ -C₄ 鹵烷基、CF₃ 或CN；R³ 為H、鹵素、C₁ -C₄ 烷基、CN或C₁ -C₄ 鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₄ 烷基；R⁷ 為視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z³ 取代之-C₀ -C₃ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基；R⁸ 為H、視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z⁴ 取代之C₂ -C₄ 烯基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基，或經0-3個T¹ 取代之5-9員橋接碳環； 各R⁹ 獨立地為H或視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基；R¹⁰ 為視情況經0-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基；Z¹ 為C₁ -C₄ 氰烷基、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為-C(O)OR⁹ ； 各Z² 獨立地為羥基、鹵素、CN； 各Z³ 獨立地為C₁ -C₄ 烷基、鹵素、C₁ -C₄ 鹵烷基、羥基、C₁ -C₄ 羥烷基、C₁ -C₄ 烷氧基或CN； 各Z⁴ 獨立地為羥基、鹵素、C₁ -C₄ 烷氧基或CN；且 各Z⁵ 獨立地為C₁ -C₄ 烷基、C₁ -C₆ 鹵烷基、羥基、C₁ -C₄ 羥烷基、鹵素、C₁ -C₄ 烷氧基、CN或C₁ -C₄ 氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、C₁ -C₄ 烷氧基或CN。實施例 5 之子實施例 Embodiment 5 of the present invention relates to a compound according to any one of the preceding embodiments, wherein: E is phenyl or 6-membered heteroaryl, wherein E is substituted with 0-1 Q, with the proviso that when E is 6 When heteroaryl, O is not attached to the heteroatom of E; G is one of the following groups: (a) C3 _{- C6} ring substituted with ^0-2 T1 and ^0-1 T2 Alkyl; (b) C ₃ -C ₆ cycloalkenyl substituted with 0-2 T ¹ and 0-1 T ² ; (c) substituted with 0-2 T ¹ and 0-1 T ² 5-9 membered bridged carbocyclic ring; (d) 5-9 membered carbocyclic spiro ring, which contains two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic spiro ring is connected by 0-2 T ¹ and 0-1 T ² substitutions; (e) 6-9 membered heterocyclic spiro rings containing two cyclic groups with at least one heteroatom, wherein the two cyclic groups consist of a common spiro carbon Atom linked, wherein the heterocyclic spiro ring system is substituted with 0-2 T ⁵ , 0-1 T ⁶ ; (f) phenyl substituted with 0-2 T ¹ and 0-1 T ⁴ ; (g) ) 4-6-membered heterocycloalkyl substituted with 0-2 T ⁵ and 0-1 T ⁶ ; (h) 4-6-membered heterocycloalkyl substituted with 0-2 T ⁵ and 0-1 T ⁶ Cycloalkenyl; (i) a 5-9 membered bridged heterocycle substituted with 0-2 T ⁵ and 0-1 T ⁶ ; or (j) substituted with 0-2 T ⁵ and 0-1 T ³ 5-6 membered heteroaryl; each Q is independently halogen, CN or C ₁ -C ₄ alkyl substituted by 1-3 halogens as appropriate; each T ¹ is independently halogen, hydroxy, optionally by 1 -C ₁ -C ₄ alkyl substituted with 3 R ^b , C ₂ -C ₄ alkenyl optionally substituted with 1-3 R ^b , C ₂ -C ₄ optionally substituted with 1-3 R ^b Alkynyl, CN, C ₁ -C ₄ cyanoalkyl, C ₁ -C ₄ alkoxy optionally substituted with 1-3 R ^b , or C ₁ -C optionally substituted with 1-3 R ^b ₄ alkoxy C ₁ -C ₄ alkyl; T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _{0- 1} -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N (R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _0-1 -C( O)R ¹⁰ , -(CH ₂ ) _0-1 -C(O)H, -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ , via 1-3 Z ³ as appropriate Substituted -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-1 -phenyl substituted with 1-3 Z ⁵ , or optionally 1-3 -(CH ₂ ) _0-1-5-6 membered heteroaryl substituted by Z ⁵ ; T ³ is -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl, optionally via 4-chloropyridine

-O-5-6-membered heterocycloalkyl substituted by -3-keto-5-yl, or -(CH ₂ ) _0-2 -5-9-membered bridged carbocycle, wherein -(CH ₂ ) _0-2 - C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-1 -5-6 membered heterocycloalkyl or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycle each optionally via 1-3 Z ⁵ and 0-1 Z ¹ substitutions, with the limitation that when T ³ is attached to the heteroatom of G, G is not attached to the oxygen or nitrogen atom of T ³ ; T ⁴ is -(CH ₂ ) _{0- 1} C(O)OR ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ , - (CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O ) N(R ⁸ )R ⁹ , or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, optionally C ₁ -C ₄ alkyl substituted with 1-3 R ^b , optionally 1 -C ₂ -C ₄ alkenyl substituted with 3 R ^b , C ₂ -C ₄ alkynyl optionally substituted with 1-3 R ^b , CN, C ₁ -C ₄ cyanoalkyl, optionally 1- C ₁ -C ₄ alkoxy substituted with 3 R ^b , or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl substituted with 1-3 R ^b as the case may be, with the limitation that when T ⁵ When attached to the heteroatom of G, T ⁵ cannot be halogen, hydroxy, CN or C ₁ -C ₄ alkoxy substituted by 1-3 R ^b as the case may be; T ⁶ is -(CH ₂ ) _0-1 - N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _0-1 -C(O)R ¹⁰ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ , -N(H)C(H)C=O, through 1-4 Z as the case may be ³ replaces -( CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-1 -5-6 membered heterocycloalkyl, optionally substituted by 1-4 Z ³ , optionally by 1- 3 Z ⁵ substituted -(CH ₂ ) _0-1-5-6 -membered heteroaryl, or 4-chloroda

-3-keto-5-yl, with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to an oxygen or nitrogen atom of T ⁶ ; R ^a is H or C ₁ -C ₄ alkyl; R ^b is F, Cl, CN, CF ₃ or hydroxyl, with the limitation that no more than one R ^b can be CF ₃ ; R ¹ is H, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl substituted with 1-3 Z ² or C ₂ -C ₄ alkyl substituted with 1-3 Z ² ; R ² is H, halogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, CF ₃ or CN; R ³ is H, halogen, C ₁ -C ₄ alkyl, CN or C ₁ - _C4 haloalkyl; each ^R4 is independently halogen, CN or _C1 - _C4 alkyl optionally substituted with 1-3 halogens; ^R7 is C1 optionally substituted with _1-3 ^Z4 -C ₄ alkyl, optionally -C ₀ -C ₃ alkyl substituted with 1-3 Z ³ -C ₃ -C ₆ cycloalkyl, optionally -C ₀ - substituted with 1-3 Z ³ C ₃ alkyl-phenyl, optionally -C ₀ -C ₁ alkyl-5-6 membered heteroaryl substituted with 1-3 Z ⁵ as appropriate, or -C substituted with 1-3 Z ⁵ as appropriate ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl; R ⁸ is H, optionally C ₁ -C ₄ alkyl substituted with 1-3 Z ⁴ , optionally substituted with 1-3 Z ⁴ C ₂ -C ₄ alkenyl, optionally -C ₀ -C ₁ alkyl-C ₃ -C ₆ cycloalkyl substituted by 1-3 Z ³ , optionally - substituted by 1-3 Z ³ C ₀ -C ₁ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₁ alkyl-5-6 membered heteroaryl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl, or a 5-9 membered bridged carbocycle substituted with 0-3 T ¹ ; each R ⁹ is independently H or optionally through 1-3 Z ⁴ substituted C ₁ -C ₄ alkyl; R ¹⁰ is optionally C ₁ -C ₄ alkyl substituted with 0-3 Z ⁴ , optionally -C ₀ - substituted with 1-3 Z ³ C ₁ alkyl-C ₃ -C ₆ cycloalkyl, optionally -C ₀ -C ₁ alkyl-phenyl substituted with 1-3 Z ³ , optionally -C substituted with 1-3 Z ⁵ ₀ -C ₁ alkyl-5-6 membered heteroaryl, or -C ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl substituted by 1-3 Z ⁵ as appropriate; Z ¹ is C ₁ -C ₄ cyanoalkyl, -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _0-1 -C(O)-N(R ⁸ )R ⁹ , with the limitation that when When Z ¹ is attached to a heteroatom, then Z ¹ is not is -C(O)OR ⁹ ; each Z ² is independently hydroxyl, halogen, CN; each Z ³ is independently C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ haloalkyl, hydroxyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, or CN; each Z ⁴ is independently hydroxy, halogen, C ₁ -C ₄ alkoxy, or CN; and each Z ⁵ is independently C ₁ -C ₄ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, C ₁ -C ₄ hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CN or C ₁ -C ₄ cyanoalkyl, subject to the limitations When Z ⁵ is attached to a heteroatom, then Z ⁵ is not halogen, hydroxy, C ₁ -C ₄ alkoxy, or CN. Sub-Example of Example 5

本發明之實施例 5 （ a ） 係關於實施例5，其中E係經0-1個Q取代之苯基。 Embodiment 5 ( a ) of the present invention relates to Embodiment 5, wherein E is phenyl substituted with 0-1 Q.

本發明之實施例 5 （ b ） 係關於實施例5，其中E係經0-1個Q取代之6員雜芳基，其限制條件為O不連接至E之雜原子。 Embodiment 5 ( b ) of the present invention relates to embodiment 5, wherein E is a 6-membered heteroaryl substituted with 0-1 Q, with the proviso that O is not attached to a heteroatom of E.

本發明之實施例 5 （ c ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基。 Embodiment 5 ( c ) of the present invention relates to embodiment 5, 5(a) or 5(b), wherein G is a C3 _{- C6} ring substituted with ^0-2 T1 and ^0-1 T2 alkyl.

本發明之實施例 5 （ d ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基。 Embodiment 5 ( d ) of the present invention relates to embodiment 5, 5(a) or 5(b), wherein G is a C3 _{- C6} ring substituted with ^0-2 T1 and ^0-1 T2 alkenyl.

本發明之實施例 5 （ e ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環。 Embodiment 5 ( e ) of the present invention relates to embodiment 5, 5(a) or 5(b), wherein G is a 5-9 membered bridging carbon substituted with ^0-2 T1 and ^0-1 T2 ring.

本發明之實施例 5 （ f ） 係關於實施例5、5（a）或5（b），其中G為含有兩個環烷基之5-9員碳環螺環，該等環烷基由一個共同螺碳原子連接，其中碳環螺環經0-2個T¹ 及0-1個T² 取代。 Embodiment 5 ( f ) of the present invention relates to embodiment 5, 5(a) or 5(b) wherein G is a 5-9 membered carbocyclic spiro ring containing two cycloalkyl groups consisting of A common spiro carbon atom is attached, wherein the carbocyclic spiro ring is substituted with 0-2 T ¹ and 0-1 T ² .

本發明之實施例 5 （ g ） 係關於實施例5、5（a）或5（b），其中G為含有兩個具有至少一個雜原子之環狀基團的6-9員雜環螺環，其中兩個環狀基團由一個共同螺碳原子連接，其中雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代。 Embodiment 5 ( g ) of the present invention relates to embodiment 5, 5(a) or 5(b), wherein G is a 6-9 membered heterocyclic spiro ring containing two cyclic groups having at least one heteroatom , wherein the two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted with 0-2 T ⁵ , 0-1 T ⁶ .

本發明之實施例 5 （ h ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T¹ 及0-1個T⁴ 取代之苯基。 Embodiment 5 ( h ) of the present invention relates to embodiment 5, 5(a) or ⁵ (b), wherein G is phenyl substituted with 0-2 T1 and ^0-1 T4.

本發明之實施例 5 （ i ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基。 Embodiment 5 ( i ) of the present invention relates to embodiment 5, 5(a) or ⁵ (b), wherein G is a ^4-6 membered heterocycle substituted with 0-2 T5 and 0-1 T6 alkyl.

本發明之實施例 5 （ j ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基。 Embodiment 5 ( j ) of the present invention relates to embodiment 5, 5(a) or ⁵ (b), wherein G is a ^4-6 membered heterocycle substituted with 0-2 T5 and 0-1 T6 alkenyl.

本發明之實施例 5 （ k ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環。 Embodiment 5 ( k ) of the present invention relates to embodiment 5, 5(a) or 5(b), wherein G is a ^5-9 membered bridging heterozygous substituted with 0-2 T5 and 0-1 ^T6 ring.

本發明之實施例 5 （ l ） 係關於實施例5、5（a）或5（b），其中G係經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 5 ( l ) of the present invention relates to embodiment 5, 5(a) or ⁵ (b), wherein G is a ^5-6 membered heteroaromatic substituted with 0-2 T5 and 0-1 T3 base.

本發明之實施例 5 （ m ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 5 ( m ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 5 （ n ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 5 ( n ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 5 （ o ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 5 ( o ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 5 （ p ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 5 ( p ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 5 （ q ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 5 ( q ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 5 （ r ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 5 ( r ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 5 （ s ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 。 Embodiment 5 ( s ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)OR ⁹ .

本發明之實施例 5 （ t ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁸ )R⁹ 。 Embodiment 5 ( t ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ .

本發明之實施例 5 （ u ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 。 Embodiment 5 ( u ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ .

本發明之實施例 5 （ v ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 5 ( v ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -C(O)OR ⁹ .

本發明之實施例 5 （ w ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 5 ( w ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 5 （ x ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)H。 Embodiment 5 ( x ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -C(O)H.

本發明之實施例 5 （ y ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 。 Embodiment 5 ( y ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 5 （ z ）係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基。 Embodiment 5 ( z ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl optionally substituted with 1-3 Z ³ .

本發明之實施例 5 （ aa ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基。 Example 5 ( aa ) of the present invention relates to a compound such as Example 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -phenyl optionally substituted with 1-3 Z ⁵ .

本發明之實施例 5 （ ab ） 係關於如實施例5、5（a）、5（b）、5（c）、5（d）、5（e）或5（f）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基。 Embodiment 5 ( ab ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(c), 5(d), 5(e) or 5(f), wherein T ² is -(CH ₂ ) _0-1 -5-6 membered heteroaryl optionally substituted with 1-3 Z ⁵ .

本發明之實施例 5 （ ac ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 5 ( ac ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or ⁵ (l), wherein T3 is -( _CH2 ) _0-2 -C(O) N(R ⁸ )R ⁹ .

本發明之實施例 5 （ ad ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為當T³ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 5 ( ad ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or ⁵ (l), wherein T3 is -( _CH2 ) _0-2 -N( ^R8 ) R ⁹ with the proviso that when T ³ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 5 （ ae ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 5 ( ae ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(l), wherein T ³ is -(CH ₂ ) _0-2 -C(O) OR ⁹ .

本發明之實施例 5 （ af ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 5 ( af ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or ⁵ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl substituted with Z ¹ .

本發明之實施例 5 （ ag ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T³ 連接至G之雜原子時，G不連接至5-6員雜環烷基之氧原子或氮原子。 Embodiment 5 ( ag ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or ⁵ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 -( _{CH 2} ⁾ _0-2-5-6 membered heterocycloalkyl substituted with Z , with the proviso that when T ³ is attached to the heteroatom of G, G is not attached to the 5-6 membered heterocycloalkyl the oxygen or nitrogen atom.

本發明之實施例 5 （ ah ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基。 Embodiment 5 ( ah ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or 5(l), wherein T3 is optionally via ⁴ -chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl.

本發明之實施例 5 （ ai ） 係關於如實施例5、5（a）、5（b）或5（l）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-9員橋接碳環。 Embodiment 5 ( ai ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or ⁵ (l), wherein T3 is optionally via ^1-3 Z5 and 0-1 Z ¹ is substituted with -(CH ₂ ) _0-2-5-9 member bridged carbocycle.

本發明之實施例 5 （ aj ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 C(O)OR⁹ 。 Embodiment 5 ( aj ) of the present invention relates to a compound as embodiment 5, 5(a), 5(b) or ⁵ (h), wherein T4 is -( _CH2 ) _0-1C (O)OR ⁹ .

本發明之實施例 5 （ ak ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 5 ( ak ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(h), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 5 （ al ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R， Embodiment 5 ( a1 ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(h), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R,

本發明之實施例 5 （ am ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 5 ( am ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(h), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 5 （ an ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 5 ( an ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(h), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ N( R ⁸ )R ⁹ .

本發明之實施例 5 （ ao ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 5 ( ao ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b) or 5(h), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 5 （ ap ） 係關於如實施例5、5（a）、5（b）或5（h）之化合物，其中T⁴ 為N(R^a )₂ 。 Embodiment 5 ( ap ) of the present invention relates to a compound as in Embodiment 5, 5(a), 5(b) or ⁵ (h), wherein T4 is N( ^Ra ) ₂ .

本發明之實施例 5 （ aq ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ -R⁷ 。 Embodiment 5 ( aq ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ - ^R7 .

本發明之實施例 5 （ ar ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 5 ( ar ) of the present invention relates to a compound as in Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 5 （ as ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 5 ( as ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 5 （ at ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 5 ( at ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 5 （ au ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 5 ( au ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N( R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 5 （ av ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R⁸ 。 Embodiment 5 ( av ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O)R ⁸ .

本發明之實施例 5 （ aw ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)OR⁹ 。 Embodiment 5 ( aw ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)OR ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O) ^OR9 .

本發明之實施例 5 （ ax ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 5 ( ax ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 5 （ ay ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 。 Embodiment 5 ( ay ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -C(O)-N(R ⁸ )R ⁹ .

本發明之實施例 5 （ az ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 5 ( az ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -C(O)OR ⁹ .

本發明之實施例 5 （ ba ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 5 ( ba ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 5 （ bb ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R¹⁰ 。 Embodiment 5 ( bb ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C( O)R ¹⁰ .

本發明之實施例 5 （ bc ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Embodiment 5 ( bc ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -N(H)C(H)C=O, with the proviso that ^T6 is not attached to a G heteroatom.

本發明之實施例 5 （ bd ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基。 Embodiment 5 ( bd ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl optionally substituted with 1-4 Z ³ .

本發明之實施例 5 （ be ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 5 ( be ) of the present invention relates to a compound such as embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -( _CH2 ) ^0-1-5-6 membered heterocycloalkyl optionally substituted with 1-4 Z3, with the proviso that when ^T6 is attached to _a heteroatom of G, G is not attached to Heteroatom of 5-6 membered heteroaryl.

本發明之實施例 5 （ bf ） 係關於如實施例5、5（a）、5（b）、5（g）、5（i）、5（j）或5（k）之化合物，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 5 ( bf ) of the present invention relates to a compound such as Embodiment 5, 5(a), 5(b), 5(g), 5(i), 5(j) or 5(k), wherein T ⁶ is -(CH ₂ ) _0-1-5-6 membered heteroaryl optionally substituted with 1-3 Z ⁵ , with the proviso that when T ⁶ is attached to the heteroatom of G, G is not attached to 5 -Heteroatom of 6-membered heteroaryl.

實施例 5 （ bg ） 係關於實施例5、5（a）、5（b）、5（c）、5（d）、5（e）、5（f）、5（g）、5（h）、5（i）、5（j）、5（k）、5（l）、5（m）、5（n）、5（o）、5（p）、5（q）、5（r）、5（s）、5（t）、5（u）、5（v）、5（w）、5（x）、5（y）、5（z）、5（aa）、5（ab）、5（ac）、5（ad）、5（ae）、5（af）、5（ag）、5（ah）、5（ai）、5（aj）、5（ak）、5（al）、5（am）、5（an）、5（ao）、5（ap）、5（aq）、5（ar）、5（as）、5（at）、5（au）、5（av）、5（aw）、5（ax）、5（ay）、5（az）、5（ba）、5（bb）、5（bc）、5（bd）、5（be）或5（bf）中之任一者，其中R¹ 為氫。 Example 5 ( bg ) relates to Examples 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h) ), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r ), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab ), 5(ac), 5(ad), 5(ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al ), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av) ), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf) ), wherein R ¹ is hydrogen.

實施例 5 （ bh ） 係關於實施例5、5（a）、5（b）、5（c）、5（d）、5（e）、5（f）、5（g）、5（h）、5（i）、5（j）、5（k）、5（l）、5（m）、5（n）、5（o）、5（p）、5（q）、5（r）、5（s）、5（t）、5（u）、5（v）、5（w）、5（x）、5（y）、5（z）、5（aa）、5（ab）、5（ac）、5（ad）、5（ae）、5（af）、5（ag）、5（ah）、5（ai）、5（aj）、5（ak）、5（al）、5（am）、5（an）、5（ao）、5（ap）、5（aq）、5（ar）、5（as）、5（at）、5（au）、5（av）、5（aw）、5（ax）、5（ay）、5（az）、5（ba）、5（bb）、5（bc）、5（bd）、5（be）或5（bf）中之任一者，其中R¹ 係經0-4個羥基取代之C₂ -C₄ 烷基。 Example 5 ( bh ) relates to Examples 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h) ), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r ), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab ), 5(ac), 5(ad), 5(ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al ), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av) ), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf) ), wherein R ¹ is C ₂ -C ₄ alkyl substituted with 0-4 hydroxy groups.

實施例 5 （ bi ） 係關於實施例5、5（a）、5（b）、5（c）、5（d）、5（e）、5（f）、5（g）、5（h）、5（i）、5（j）、5（k）、5（l）、5（m）、5（n）、5（o）、5（p）、5（q）、5（r）、5（s）、5（t）、5（u）、5（v）、5（w）、5（x）、5（y）、5（z）、5（aa）、5（ab）、5（ac）、5（ad）、5（ae）、5（af）、5（ag）、5（ah）、5（ai）、5（aj）、5（ak）、5（al）、5（am）、5（an）、5（ao）、5（ap）、5（aq）、5（ar）、5（as）、5（at）、5（au）、5（av）、5（aw）、5（ax）、5（ay）、5（az）、5（ba）、5（bb）、5（bc）、5（bd）、5（be）或5（bf）中之任一者，其中R² 為鹵素。 Example 5 ( bi ) relates to Examples 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h ), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r ), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab ), 5(ac), 5(ad), 5(ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al ), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av) ), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf) ), wherein R ² is halogen.

實施例 5 （ bj ） 係關於實施例5、5（a）、5（b）、5（c）、5（d）、5（e）、5（f）、5（g）、5（h）、5（i）、5（j）、5（k）、5（l）、5（m）、5（n）、5（o）、5（p）、5（q）、5（r）、5（s）、5（t）、5（u）、5（v）、5（w）、5（x）、5（y）、5（z）、5（aa）、5（ab）、5（ac）、5（ad）、5（ae）、5（af）、5（ag）、5（ah）、5（ai）、5（aj）、5（ak）、5（al）、5（am）、5（an）、5（ao）、5（ap）、5（aq）、5（ar）、5（as）、5（at）、5（au）、5（av）、5（aw）、5（ax）、5（ay）、5（az）、5（ba）、5（bb）、5（bc）、5（bd）、5（be）或5（bf）中之任一者，其中R² 為CN。 Example 5 ( bj ) relates to Examples 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h ), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r ), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab ), 5(ac), 5(ad), 5(ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al ), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av) ), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf) ), wherein R ² is CN.

實施例 5 （ bk ） 係關於實施例5、5（a）、5（b）、5（c）、5（d）、5（e）、5（f）、5（g）、5（h）、5（i）、5（j）、5（k）、5（l）、5（m）、5（n）、5（o）、5（p）、5（q）、5（r）、5（s）、5（t）、5（u）、5（v）、5（w）、5（x）、5（y）、5（z）、5（aa）、5（ab）、5（ac）、5（ad）、5（ae）、5（af）、5（ag）、5（ah）、5（ai）、5（aj）、5（ak）、5（al）、5（am）、5（an）、5（ao）、5（ap）、5（aq）、5（ar）、5（as）、5（at）、5（au）、5（av）、5（aw）、5（ax）、5（ay）、5（az）、5（ba）、5（bb）、5（bc）、5（bd）、5（be）或5（bf）中之任一者，其中R³ 為H。 Example 5 ( bk ) relates to Examples 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h ), 5(i), 5(j), 5(k), 5(l), 5(m), 5(n), 5(o), 5(p), 5(q), 5(r ), 5(s), 5(t), 5(u), 5(v), 5(w), 5(x), 5(y), 5(z), 5(aa), 5(ab ), 5(ac), 5(ad), 5(ae), 5(af), 5(ag), 5(ah), 5(ai), 5(aj), 5(ak), 5(al ), 5(am), 5(an), 5(ao), 5(ap), 5(aq), 5(ar), 5(as), 5(at), 5(au), 5(av) ), 5(aw), 5(ax), 5(ay), 5(az), 5(ba), 5(bb), 5(bc), 5(bd), 5(be), or 5(bf) ), wherein ^R is H.

此實施例之實施例 6 係 關於如前述實施例1、2、3、4或5中任一項之化合物，其中R¹ 為氫。 Embodiment 6 of this embodiment relates to a compound as in any of the preceding Embodiments ¹ , 2, 3, 4 or 5, wherein R1 is hydrogen.

此實施例之實施例 7 係關於如實施例1、2、3、4或5中任一項之化合物，其中R¹ 係C₁ -C₄ 烷氧基C₁ -C₄ 烷基、經1-3個Z² 取代之C₂ -C₄ 烯基或經1-3個Z² 取代之C₂ -C₄ 烷基； Embodiment 7 of this embodiment relates to a compound as any one of Embodiments 1, 2, 3, 4, or 5, wherein R ¹ is C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, through 1 -C ₂ -C ₄ alkenyl substituted with 3 Z ² or C ₂ -C ₄ alkyl substituted with 1-3 Z ² ;

本發明之實施例 8 係關於如實施例1、2、3、4或5中任一項之化合物，其中 R¹ 係-CH₂ CH₂ OH、-CH₂ CH₂ CH₂ OH、-CH₂ CH(OH)CH₂ OH，或-CH₂ CH(CH₃ )OH； R² 係Cl、Br、CF₃ 或CN；且 E係吡啶基、苯基、嘧啶基或嗒

基。 Embodiment 8 of the present invention relates to a compound of any one of embodiments 1, ₂ , ₃ , ₄ or ₅ , wherein R1 is ^-CH2CH2OH , _-CH2CH2CH2OH , _{-CH2 CH} (OH)CH2OH, or -CH2CH( _{CH3 )} OH ^; R2 is Cl, Br, _CF3 , or CN; and E is pyridyl, phenyl, pyrimidinyl, or pyridyl

base.

本發明之實施例 8 （ a ） 係關於實施例8，其中R¹ 為-CH₂ CH₂ OH；R² 為Cl；且E係吡啶基。 Embodiment 8 ( a ) of the present invention relates to Embodiment 8, wherein R ¹ is -CH ₂ CH ₂ OH; R ² is Cl; and E is pyridyl.

本發明之實施例 8 （ b ） 係關於實施例8，其中R¹ 為CH₂ CH₂ CH₂ OH；R² 為Cl；且E係吡啶基。 Embodiment 8 ( b ) of the present invention relates to Embodiment 8, wherein R ¹ is CH ₂ CH ₂ CH ₂ OH; R ² is Cl; and E is pyridyl.

本發明之實施例 8 （ c ） 係關於實施例8，其中R¹ 為CH₂ CH(OH)CH₂ OH；R² 為Cl；且E係吡啶基。 Embodiment 8 ( c ) of the present invention relates to Embodiment 8, wherein R ¹ is CH ₂ CH(OH)CH ₂ OH; R ² is Cl; and E is pyridyl.

本發明之實施例 8 （ d ） 係關於實施例8，其中R¹ 為CH₂ CH(CH₃ )OH；R² 為Cl；且E係吡啶基。 Embodiment 8 ( d ) of the present invention relates to Embodiment 8, wherein R ¹ is CH ₂ CH(CH ₃ )OH; R ² is Cl; and E is pyridyl.

本發明之實施例 9 係關於如實施例8之化合物，其中R² 為Cl。 Embodiment 9 of the present invention relates to a compound as embodiment ⁸ , wherein R2 is Cl.

本發明之實施例 10 係關於如實施例1、2、3、4或5中任一項之化合物，其中 R¹ 係H； R² 係Cl、Br、CF₃ 或CN； R⁴ 係鹵素；且 E係吡啶基、苯基、嘧啶基或嗒

基。實施例 10 之子實施例 Embodiment 10 of the present invention relates to a compound as in any one of Embodiments 1, 2, 3, 4 or 5, wherein R ¹ is H; R ² is Cl, Br, CF ₃ or CN; R ⁴ is halogen; and E is pyridyl, phenyl, pyrimidinyl or pyridyl

base. Sub-Example of Example 10

本發明之實施例 10 （ a ） 係關於實施例10，其中E係吡啶基。 Embodiment 10 ( a ) of the present invention relates to Embodiment 10, wherein E is pyridyl.

本發明之實施例 11 係關於如實施例 10 之化合物，其中R² 為Cl。 Embodiment 11 of the present invention relates to a ^compound as embodiment 10 , wherein R2 is Cl.

本發明之實施例 12 係關於如實施例 1 至 5 中任一項之化合物，其具有下式中之任一者：

,實施例 12 之子實施例 Embodiment 12 of the present invention relates to a compound as any one of Embodiments 1 to 5 having any of the following formulae:

, a sub-embodiment of embodiment 12

本發明之實施例 12 （ a ） 係關於實施例12，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基。 Embodiment 12 ( a ) of the present invention relates to embodiment 12, wherein G is C3 _{- C6} cycloalkyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 12 （ b ） 係關於實施例12，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基。 Embodiment 12 ( b ) of the present invention relates to embodiment 12, wherein G is C3 _{- C6} cycloalkenyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 12 （ c ） 係關於實施例12，其中G係經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環。 Embodiment 12 ( c ) of the present invention relates to embodiment 12, wherein G is a 5-9 membered bridged carbocycle substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 12 （ d ） 係關於實施例12，其中G為含有兩個環烷基之5-9員碳環螺環，該等環烷基由一個共同螺碳原子連接，其中碳環螺環係經0-2個T¹ 及0-1個T² 取代。 Embodiment 12 ( d ) of the present invention relates to Embodiment 12, wherein G is a 5-9 membered carbocyclic spiro ring containing two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic The spiro ring system is substituted with 0-2 T ¹ and 0-1 T ² .

本發明之實施例 12 （ e ） 係關於實施例12，其中G為含有兩個具有至少一個雜原子之環狀基團的6-9員雜環螺環，其中兩個環狀基團由一個共同螺碳原子連接，其中雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代。 Embodiment 12 ( e ) of the present invention relates to embodiment 12, wherein G is a 6-9 membered heterocyclic spiro ring containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups consist of a A common spiro carbon atom is attached, wherein the heterocyclic spiro ring system is substituted with 0-2 ^T5 , 0-1 ^T6 .

本發明之實施例 12 （ f ） 係關於實施例12，其中G係經0-2個T¹ 及0-1個T⁴ 取代之苯基。 Embodiment 12 ( f ) of the present invention relates to embodiment ¹² , wherein G is phenyl substituted with 0-2 T1 and ^0-1 T4.

本發明之實施例 12 （ g ） 係關於實施例12，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基。 Embodiment 12 ( g ) of the present invention relates to embodiment ¹² , wherein G is a ^4-6 membered heterocycloalkyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 12 （ h ） 係關於實施例12，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基。 Embodiment 12 ( h ) of the present invention relates to embodiment ¹² , wherein G is a ^4-6 membered heterocycloalkenyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 12 （ i ） 係關於實施例12，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環。 Embodiment 12 ( i ) of the present invention relates to embodiment 12, wherein G is a ^5-9 membered bridged heterocycle substituted with 0-2 T5 and 0-1 ^T6 .

本發明之實施例 12 （ j ） 係關於實施例12，其中G係經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 12 ( j ) of the present invention relates to embodiment ¹² , wherein G is a ^5-6 membered heteroaryl substituted with 0-2 T5 and 0-1 T3.

本發明之實施例 12 （ k ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 12 ( k ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T2 is -( ^CH2 _{) 0-1} -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 12 （ l ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 12 ( l ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 12 （ m ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 12 ( m ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T2 is -( ^CH2 _{) 0-1} -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 12 （ n ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 12 ( n ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T2 is -( ^CH2 _{) 0-1} -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 12 （ o ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 12 ( o ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 12 （ p ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 12 ( p ) of the present invention relates to a compound such as Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -N( ^R9 )C(O) ^R8 .

本發明之實施例 12 （ q ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 。 Embodiment 12 ( q ) of the present invention relates to a compound such as Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -N( ^R9 )C(O) ^OR9 .

本發明之實施例 12 （ r ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁸ )R⁹ 。 Embodiment 12 ( r ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T2 is -( ^CH2 _{) 0-1} -N(R ⁸ )R ⁹ .

本發明之實施例 12 （ s ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 。 Embodiment 12 ( s ) of the present invention relates to a compound such as Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ .

本發明之實施例 12 （ t ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 12 ( t ) of the present invention relates to a compound such as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)OR ⁹ .

本發明之實施例 12 （ u ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 12 ( u ) of the present invention relates to a compound such as Embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 12 （ v ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)H。 Embodiment 12 ( v ) of the present invention relates to a compound as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)H.

本發明之實施例 12 （ w ） 係關於如實施例12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 。 Embodiment 12 ( w ) of the present invention relates to a compound as embodiment 12, 12(a), 12(b), 12(c) or 12(d), wherein T2 is -( ^CH2 _{) 0-1} -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 12 （ x ） 係關於如實施例5、12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基。 Embodiment 12 ( x ) of the present invention relates to a compound such as Embodiment 5, 12, 12(a), 12(b), 12(c) or ¹² (d), wherein T2 is optionally modified from 1-3 -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl substituted with Z ³ .

本發明之實施例 12 （ y ） 係關於如12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基。 Embodiment 12 ( y ) of the present invention relates to compounds such as 12, 12(a), 12(b), 12(c) or ¹² ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 -(CH ₂ ) _0-1 -phenyl.

本發明之實施例 12 （ z ） 係關於如12、12（a）、12（b）、12（c）或12（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基。 Embodiment 12 ( z ) of the present invention relates to compounds such as 12, 12(a), 12(b), 12(c) or ¹² ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 The -(CH ₂ ) _0-1-5-6 membered heteroaryl.

本發明之實施例 12 （ aa ） 係關於如實施例12或12（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 12 ( aa ) of the present invention relates to a compound as embodiment 12 or ¹² (j), wherein T3 is -( _CH2 ) _0-2 -C(O)N( ^R8 ) ^R9 .

本發明之實施例 12 （ ab ） 係關於如實施例12或12（j）之化合物，其中T³ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為當T³ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 12 ( ab ) of the present invention relates to the compound as embodiment 12 or 12(j), wherein T ³ is -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , with the limitation that when T When ³ is attached to the heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 12 （ ac ） 係關於如實施例12或12（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 12 ( ac ) of the present invention relates to a compound as embodiment 12 or ¹² (j), wherein T3 is -( _CH2 ) _0-2 -C(O) ^OR9 .

本發明之實施例 12 （ ad ） 係關於如實施例12或12（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 12 ( ad ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T3 is ^- ( _CH2 ) optionally substituted with ^1-3 Z5 and ^0-1 Z1 _{0-2 -} C3 _- C6cycloalkyl.

本發明之實施例 12 （ ae ） 係關於如實施例12或12（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T³ 連接至G之雜原子時，G不連接至5-6員雜環烷基之氧原子或氮原子。 Embodiment 12 ( ae ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-6 membered heterocycloalkyl with the proviso that when T3 is attached to a heteroatom ^of G, G is not attached to an oxygen or nitrogen atom of the 5-6 membered heterocycloalkyl.

本發明之實施例 12 （ af ） 係關於如實施例12或12（j）之化合物，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基。 Embodiment 12 ( af ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T3 is optionally via ⁴ -chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl.

本發明之實施例 12 （ ag ） 係關於如實施例12或12（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-9員橋接碳環。 Embodiment 12 ( ag ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-9 member bridged carbon rings.

本發明之實施例 12 （ ah ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 C(O)OR⁹ 。 Embodiment 12 ( ah ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T4 is ^- ( _CH2 ) _0-1C (O) ^OR9 .

本發明之實施例 12 （ ai ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 12 ( ai ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 12 （ aj ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R， Embodiment 12 ( aj ) of the present invention relates to a compound such as embodiment 12 or 12(j), wherein T4 is ^- ( _CH2 ) _0-1 -N( ^R9 )SO2 _- R,

本發明之實施例 12 （ ak ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 12 ( ak ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T4 is ^- ( _CH2 ) _0-1 -SO2 _- ^R7 .

本發明之實施例 12 （ al ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 12 ( a1 ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 12 （ am ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 12 ( am ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 12 （ an ） 係關於如實施例12或12（j）之化合物，其中T⁴ 為N(R^a )₂ 。 Embodiment 12 ( an ) of the present invention relates to a compound as embodiment 12 or 12(j), wherein T4 is N(R ^a _{) 2} ^.

本發明之實施例 12 （ ao ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ -R⁷ 。 Embodiment 12 ( ao ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 12 （ ap ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 12 ( ap ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 12 （ aq ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 12 ( aq ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 12 （ ar ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 12 ( ar ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ . The limitation is that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )SO2N ₍ ^R8 ) ^R9 .

本發明之實施例 12 （ as ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 12 ( as ) of the present invention relates to a compound such as Embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 12 （ at ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R⁸ 。 Embodiment 12 ( at ) of the present invention relates to a compound as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -N( ^R9 )C(O) ^R8 with the proviso that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )C(O) ^R8 .

本發明之實施例 12 （ au ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)OR⁹ 。 Embodiment 12 ( au ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)OR ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)OR ⁹ .

本發明之實施例 12 （ av ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 12 ( av ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 12 （ aw ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 。 Embodiment 12 ( aw ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)-N(R ⁸ )R ⁹ .

本發明之實施例 12 （ ax ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 12 ( ax ) of the present invention relates to a compound such as Embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)OR ⁹ .

本發明之實施例 12 （ ay ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 12 ( ay ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 12 （ az ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R¹⁰ 。 Embodiment 12 ( az ) of the present invention relates to a compound such as Embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 12 （ ba ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Embodiment 12 ( ba ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is -N(H)C(H )C=O, with the proviso that ^T6 is not attached to a G heteroatom.

本發明之實施例 12 （ bb ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基。 Embodiment 12 ( bb ) of the present invention relates to a compound as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is optionally via 1-4 Z ³ -substituted -(CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl.

本發明之實施例 12 （ bc ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 12 ( bc ) of the present invention relates to a compound as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is optionally through 1-4 Z ³ -substituted -(CH ₂ ) _0-1-5-6 membered heterocycloalkyl, with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to a heteroatom of a 5-6 membered heteroaryl .

本發明之實施例 12 （ bd ） 係關於如實施例12、12（e）、12（g）、12（h）或12（i）之化合物，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 12 ( bd ) of the present invention relates to a compound such as embodiment 12, 12(e), 12(g), 12(h) or 12(i), wherein ^T6 is optionally through 1-3 Z ⁵ -substituted -( _CH2 ) _0-1-5-6 membered heteroaryl, with the proviso that when ^T6 is attached to the heteroatom of G, G is not attached to the heteroatom of the 5-6 membered heteroaryl.

實施例 12 （ be ） 係關於實施例12、12（a）、12（b）、12（c）、12（d）、12（e）、12（f）、12（g）、12（h）、12（i）、12（j）、12（k）、12（l）、12（m）、12（n）、12（o）、12（p）、12（q）、12（r）、12（s）、12（t）、12（u）、12（v）、12（w）、12（x）、12（y）、12（z）、12（aa）、12（ab）、12（ac）、12（ad）、12（ae）、12（af）、12（ag）、12（ah）、12（ai）、12（aj）、12（ak）、12（al）、12（am）、12（an）、12（ao）、12（ap）、12（aq）、12（ar）、12（as）、12（at）、12（au）、12（av）、12（aw）、12（ax）、12（ay）、12（az）、12（ba）、12（bb）、12（bc）或12（bd）中之任一者，其中R¹ 為氫。 Example 12 ( be ) is about Examples 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h) ), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r ), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab ), 12(ac), 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al ), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av) ), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc) or 12(bd), where R ¹ for hydrogen.

實施例 12 （ bf ） 係關於實施例12、12（a）、12（b）、12（c）、12（d）、12（e）、12（f）、12（g）、12（h）、12（i）、12（j）、12（k）、12（l）、12（m）、12（n）、12（o）、12（p）、12（q）、12（r）、12（s）、12（t）、12（u）、12（v）、12（w）、12（x）、12（y）、12（z）、12（aa）、12（ab）、12（ac）、12（ad）、12（ae）、12（af）、12（ag）、12（ah）、12（ai）、12（aj）、12（ak）、12（al）、12（am）、12（an）、12（ao）、12（ap）、12（aq）、12（ar）、12（as）、12（at）、12（au）、12（av）、12（aw）、12（ax）、12（ay）、12（az）、12（ba）、12（bb）、12（bc）或12（bd）中之任一者，其中R¹ 係經0-4個羥基取代之C₂ -C₄ 烷基。 Example 12 ( bf ) relates to Examples 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h) ), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r ), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab ), 12(ac), 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al ), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av) ), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc) or 12(bd), where R ¹ C ₂ -C ₄ alkyl substituted with 0-4 hydroxy groups.

實施例 12 （ bg ） 係關於實施例12、12（a）、12（b）、12（c）、12（d）、12（e）、12（f）、12（g）、12（h）、12（i）、12（j）、12（k）、12（l）、12（m）、12（n）、12（o）、12（p）、12（q）、12（r）、12（s）、12（t）、12（u）、12（v）、12（w）、12（x）、12（y）、12（z）、12（aa）、12（ab）、12（ac）、12（ad）、12（ae）、12（af）、12（ag）、12（ah）、12（ai）、12（aj）、12（ak）、12（al）、12（am）、12（an）、12（ao）、12（ap）、12（aq）、12（ar）、12（as）、12（at）、12（au）、12（av）、12（aw）、12（ax）、12（ay）、12（az）、12（ba）、12（bb）、12（bc）或12（bd）中之任一者，其中R² 為Cl。 Example 12 ( bg ) relates to Examples 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h) ), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r ), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab ), 12(ac), 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al ), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av) ), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc) or 12(bd), where R ² is Cl.

實施例 12 （ bh ） 係關於實施例12、12（a）、12（b）、12（c）、12（d）、12（e）、12（f）、12（g）、12（h）、12（i）、12（j）、12（k）、12（l）、12（m）、12（n）、12（o）、12（p）、12（q）、12（r）、12（s）、12（t）、12（u）、12（v）、12（w）、12（x）、12（y）、12（z）、12（aa）、12（ab）、12（ac）、12（ad）、12（ae）、12（af）、12（ag）、12（ah）、12（ai）、12（aj）、12（ak）、12（al）、12（am）、12（an）、12（ao）、12（ap）、12（aq）、12（ar）、12（as）、12（at）、12（au）、12（av）、12（aw）、12（ax）、12（ay）、12（az）、12（ba）、12（bb）、12（bc）或12（bd）中之任一者，其中R² 為CN。 Example 12 ( bh ) relates to Examples 12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g), 12(h ), 12(i), 12(j), 12(k), 12(l), 12(m), 12(n), 12(o), 12(p), 12(q), 12(r ), 12(s), 12(t), 12(u), 12(v), 12(w), 12(x), 12(y), 12(z), 12(aa), 12(ab ), 12(ac), 12(ad), 12(ae), 12(af), 12(ag), 12(ah), 12(ai), 12(aj), 12(ak), 12(al ), 12(am), 12(an), 12(ao), 12(ap), 12(aq), 12(ar), 12(as), 12(at), 12(au), 12(av) ), 12(aw), 12(ax), 12(ay), 12(az), 12(ba), 12(bb), 12(bc) or 12(bd), where R ² for CN.

實施例 13 係關於如實施例 1 至 5 中任一項之化合物，其具有下式中之任一者：

, 或其醫藥學上可接受之鹽，其中R² 為Cl、Br、CF₃ 或CN。實施例 13 之子實施例 Embodiment 13 relates to a compound as any one of Embodiments 1 to 5 having any of the following formulae:

, or a pharmaceutically acceptable salt thereof, wherein R ² is Cl, Br, CF ₃ or CN. Sub-Example of Example 13

本發明之實施例 13 （ a ） 係關於實施例13，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基。 Embodiment 13 ( a ) of the present invention relates to embodiment 13, wherein G is C3 _{- C6} cycloalkyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 13 （ b ） 係關於實施例13，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基。 Embodiment 13 ( b ) of the present invention relates to embodiment 13, wherein G is C3 _{- C6} cycloalkenyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 13 （ c ） 係關於實施例13，其中G係經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環。 Embodiment 13 ( c ) of the present invention relates to embodiment 13, wherein G is a 5-9 membered bridged carbocycle substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 13 （ d ） 係關於實施例13，其中G為含有兩個環烷基之5-9員碳環螺環，該等環烷基由一個共同螺碳原子連接，其中碳環螺環經0-2個T¹ 及0-1個T² 取代。 Embodiment 13 ( d ) of the present invention relates to Embodiment 13, wherein G is a 5-9 membered carbocyclic spiro ring containing two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic The spiro ring is substituted with 0-2 T ¹ and 0-1 T ² .

本發明之實施例 13 （ e ） 係關於實施例13，其中G為含有兩個具有至少一個雜原子之環狀基團的6-9員雜環螺環，其中兩個環狀基團由一個共同螺碳原子連接，其中雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代。 Embodiment 13 ( e ) of the present invention relates to embodiment 13, wherein G is a 6-9 membered heterocyclic spiro ring containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups consist of a A common spiro carbon atom is attached, wherein the heterocyclic spiro ring system is substituted with 0-2 ^T5 , 0-1 ^T6 .

本發明之實施例 13 （ f ） 係關於實施例13，其中G係經0-2個T¹ 及0-1個T⁴ 取代之苯基。 Embodiment 13 ( f ) of the present invention relates to embodiment ¹³ , wherein G is phenyl substituted with 0-2 T1 and ^0-1 T4.

本發明之實施例 13 （ g ） 係關於實施例13，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基。 Embodiment 13 ( g ) of the present invention relates to embodiment ¹³ , wherein G is a ^4-6 membered heterocycloalkyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 13 （ h ） 係關於實施例13，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基。 Embodiment 13 ( h ) of the present invention relates to embodiment ¹³ , wherein G is a ^4-6 membered heterocycloalkenyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 13 （ i ） 係關於實施例13，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環。 Embodiment 13 ( i ) of the present invention relates to embodiment 13, wherein G is a ^5-9 membered bridged heterocycle substituted with 0-2 T5 and 0-1 ^T6 .

本發明之實施例 13 （ j ） 係關於實施例13，其中G係經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 13 ( j ) of the present invention relates to embodiment ¹³ , wherein G is a ^5-6 membered heteroaryl substituted with 0-2 T5 and 0-1 T3.

本發明之實施例 13 （ k ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 13 ( k ) of the present invention relates to a compound such as Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 13 （ l ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 13 ( l ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 13 （ m ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 13 ( m ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 13 （ n ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 13 ( n ) of the present invention relates to a compound as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 13 （ o ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 13 ( o ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 13 （ p ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 13 ( p ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N( ^R9 )C(O) ^R8 .

本發明之實施例 13 （ q ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 。 Embodiment 13 ( q ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N( ^R9 )C(O) ^OR9 .

本發明之實施例 13 （ r ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁸ )R⁹ 。 Embodiment 13 ( r ) of the present invention relates to a compound such as Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ .

本發明之實施例 13 （ s ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 。 Embodiment 13 ( s ) of the present invention relates to a compound such as Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ .

本發明之實施例 13 （ t ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 13 ( t ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)OR ⁹ .

本發明之實施例 13 （ u ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 13 ( u ) of the present invention relates to a compound such as Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 13 （ v ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)H。 Embodiment 13 ( v ) of the present invention relates to a compound such as embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)H.

本發明之實施例 13 （ w ） 係關於如實施例13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 。 Embodiment 13 ( w ) of the present invention relates to a compound such as Embodiment 13, 13(a), 13(b), 13(c) or 13(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 13 （ x ） 係關於如實施例5、13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基。 Embodiment 13 ( x ) of the present invention relates to a compound such as Embodiment 5, 13, 13(a), 13(b), 13(c) or ¹³ (d), wherein T2 is optionally modified from 1-3 -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl substituted with Z ³ .

本發明之實施例 13 （ y ） 係關於如13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基。 Embodiment 13 ( y ) of the present invention relates to compounds such as 13, 13(a), 13(b), 13(c) or ¹³ ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 -(CH ₂ ) _0-1 -phenyl.

本發明之實施例 13 （ z ） 係關於如13、13（a）、13（b）、13（c）或13（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基。 Embodiment 13 ( z ) of the present invention relates to compounds such as 13, 13(a), 13(b), 13(c) or ¹³ ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 The -(CH ₂ ) _0-1-5-6 membered heteroaryl.

本發明之實施例 13 （ aa ） 係關於如實施例13或13（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 13 ( aa ) of the present invention relates to a compound as embodiment 13 or ¹³ (j), wherein T3 is -( _CH2 ) _0-2 -C(O)N( ^R8 ) ^R9 .

本發明之實施例 13 （ ab ） 係關於如實施例13或13（j）之化合物，其中T³ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為當T³ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 13 ( ab ) of the present invention relates to the compound as embodiment 13 or 13(j), wherein T ³ is -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , with the limitation that when T When ³ is attached to the heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 13 （ ac ） 係關於如實施例13或13（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 13 ( ac ) of the present invention relates to a compound as embodiment 13 or ¹³ (j), wherein T3 is -( _CH2 ) _0-2 -C(O) ^OR9 .

本發明之實施例 13 （ ad ） 係關於如實施例13或13（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 13 ( ad ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T3 is ^- ( _CH2 ) optionally substituted with ^1-3 Z5 and ^0-1 Z1 _{0-2 -} C3 _- C6cycloalkyl.

本發明之實施例 13 （ ee ） 係關於如實施例13或13（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T³ 連接至G之雜原子時，G不連接至5-6員雜環烷基之氧原子或氮原子。 Embodiment 13 ( ee ) of the present invention relates to the compound as embodiment 13 or 13(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-6 membered heterocycloalkyl with the proviso that when T3 is attached to a heteroatom ^of G, G is not attached to an oxygen or nitrogen atom of the 5-6 membered heterocycloalkyl.

本發明之實施例 13 （ af ） 係關於如實施例13或13（j）之化合物，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基。 Embodiment 13 ( af ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T3 is optionally via ⁴ -chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl.

本發明之實施例 13 （ ag ） 係關於如實施例13或13（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-9員橋接碳環。 Embodiment 13 ( ag ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-9 member bridged carbon rings.

本發明之實施例 13 （ ah ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 C(O)OR⁹ 。 Embodiment 13 ( ah ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T4 is ^- ( _CH2 ) _0-1C (O) ^OR9 .

本發明之實施例 13 （ ai ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 13 ( ai ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 13 （ aj ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R。 Embodiment 13 ( aj ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T4 is ^- ( _CH2 ) _0-1 -N( ^R9 )SO2 _- R.

本發明之實施例 13 （ ak ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 13 ( ak ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 13 （ al ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 13 ( a1 ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 13 （ am ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 13 ( am ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 13 （ an ） 係關於如實施例13或13（j）之化合物，其中T⁴ 為N(R^a )₂ 。 Embodiment 13 ( an ) of the present invention relates to a compound as embodiment 13 or 13(j), wherein T ⁴ is N(R ^a ) ₂ .

本發明之實施例 13 （ ao ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ -R⁷ 。 Embodiment 13 ( ao ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 13 （ ap ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 13 ( ap ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 13 （ aq ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 13 ( aq ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 13 （ ar ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 13 ( ar ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ . The limitation is that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )SO2N ₍ ^R8 ) ^R9 .

本發明之實施例 13 （ as ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 13 ( as ) of the present invention relates to a compound such as Embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 13 （ at ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R⁸ 。 Embodiment 13 ( at ) of the present invention relates to a compound as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -N( ^R9 )C(O) ^R8 with the proviso that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )C(O) ^R8 .

本發明之實施例 13 （ au ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)OR⁹ 。 Embodiment 13 ( au ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)OR ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)OR ⁹ .

本發明之實施例 13 （ av ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 13 ( av ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 13 （ aw ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 。 Embodiment 13 ( aw ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)-N(R ⁸ )R ⁹ .

本發明之實施例 13 （ ax ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 13 ( ax ) of the present invention relates to a compound such as Embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)OR ⁹ .

本發明之實施例 13 （ ay ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 13 ( ay ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 13 （ az ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R¹⁰ 。 Embodiment 13 ( az ) of the present invention relates to a compound such as Embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 13 （ ba ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Embodiment 13 ( ba ) of the present invention relates to a compound as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is -N(H)C(H )C=O, with the proviso that ^T6 is not attached to a G heteroatom.

本發明之實施例 13 （ bb ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基。 Embodiment 13 ( bb ) of the present invention relates to a compound as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is optionally via 1-4 Z ³ -substituted -(CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl.

本發明之實施例 13 （ bc ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 13 ( bc ) of the present invention relates to a compound as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is optionally through 1-4 Z ³ -substituted -(CH ₂ ) _0-1-5-6 membered heterocycloalkyl, with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to a heteroatom of a 5-6 membered heteroaryl .

本發明之實施例 13 （ bd ） 係關於如實施例13、13（e）、13（g）、13（h）或13（i）之化合物，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 13 ( bd ) of the present invention relates to a compound such as embodiment 13, 13(e), 13(g), 13(h) or 13(i), wherein ^T6 is optionally through 1-3 Z ⁵ -substituted -( _CH2 ) _0-1-5-6 membered heteroaryl, with the proviso that when ^T6 is attached to the heteroatom of G, G is not attached to the heteroatom of the 5-6 membered heteroaryl.

實施例 13 （ be ） 係關於實施例13、13（a）、13（b）、13（c）、13（d）、13（e）、13（f）、13（g）、13（h）、13（i）、13（j）、13（k）、13（l）、13（m）、13（n）、13（o）、13（p）、13（q）、13（r）、13（s）、13（t）、13（u）、13（v）、13（w）、13（x）、13（y）、13（z）、13（aa）、13（ab）、13（ac）、13（ad）、13（ae）、13（af）、13（ag）、13（ah）、13（ai）、13（aj）、13（ak）、13（al）、13（am）、13（an）、13（ao）、13（ap）、13（aq）、13（ar）、13（as）、13（at）、13（au）、13（av）、13（aw）、13（ax）、13（ay）、13（az）、13（ba）、13（bb）、13（bc）或13（bd）中之任一者，其中R² 為Cl。 Example 13 ( be ) relates to examples 13, 13(a), 13(b), 13(c), 13(d), 13(e), 13(f), 13(g), 13(h) ), 13(i), 13(j), 13(k), 13(l), 13(m), 13(n), 13(o), 13(p), 13(q), 13(r ), 13(s), 13(t), 13(u), 13(v), 13(w), 13(x), 13(y), 13(z), 13(aa), 13(ab ), 13(ac), 13(ad), 13(ae), 13(af), 13(ag), 13(ah), 13(ai), 13(aj), 13(ak), 13(al ), 13(am), 13(an), 13(ao), 13(ap), 13(aq), 13(ar), 13(as), 13(at), 13(au), 13(av) ), 13(aw), 13(ax), 13(ay), 13(az), 13(ba), 13(bb), 13(bc) or 13(bd), where R ² is Cl.

實施例 13 （ bf ） 係關於實施例13、13（a）、13（b）、13（c）、13（d）、13（e）、13（f）、13（g）、13（h）、13（i）、13（j）、13（k）、13（l）、13（m）、13（n）、13（o）、13（p）、13（q）、13（r）、13（s）、13（t）、13（u）、13（v）、13（w）、13（x）、13（y）、13（z）、13（aa）、13（ab）、13（ac）、13（ad）、13（ae）、13（af）、13（ag）、13（ah）、13（ai）、13（aj）、13（ak）、13（al）、13（am）、13（an）、13（ao）、13（ap）、13（aq）、13（ar）、13（as）、13（at）、13（au）、13（av）、13（aw）、13（ax）、13（ay）、13（az）、13（ba）、13（bb）、13（bc）或13（bd）中之任一者，其中R² 為CN。 Example 13 ( bf ) relates to Examples 13, 13(a), 13(b), 13(c), 13(d), 13(e), 13(f), 13(g), 13(h ), 13(i), 13(j), 13(k), 13(l), 13(m), 13(n), 13(o), 13(p), 13(q), 13(r ), 13(s), 13(t), 13(u), 13(v), 13(w), 13(x), 13(y), 13(z), 13(aa), 13(ab ), 13(ac), 13(ad), 13(ae), 13(af), 13(ag), 13(ah), 13(ai), 13(aj), 13(ak), 13(al ), 13(am), 13(an), 13(ao), 13(ap), 13(aq), 13(ar), 13(as), 13(at), 13(au), 13(av) ), 13(aw), 13(ax), 13(ay), 13(az), 13(ba), 13(bb), 13(bc) or 13(bd), where R ² for CN.

實施例 14 係關於如實施例 1 至 5 中任一項之化合物，其具有下式中之任一者：

. 或其醫藥學上可接受之鹽，其中R² 係Cl、Br、CF₃ 或CN。實施例 14 之子實施例 Embodiment 14 relates to a compound as any one of Embodiments 1 to 5 having any of the following formulae:

. or a pharmaceutically acceptable salt thereof, wherein R ² is Cl, Br, CF ₃ or CN. Sub-Example of Example 14

本發明之實施例 14 （ a ） 係關於實施例14，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基。 Embodiment 14 ( a ) of the present invention relates to embodiment 14, wherein G is C3 _{- C6} cycloalkyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 14 （ b ） 係關於實施例14，其中G係經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基。 Embodiment 14 ( b ) of the present invention relates to embodiment 14, wherein G is C3 _{- C6} cycloalkenyl substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 14 （ c ） 係關於實施例14，其中G係經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環。 Embodiment 14 ( c ) of the present invention relates to embodiment 14, wherein G is a 5-9 membered bridged carbocycle substituted with ^0-2 T1 and ^0-1 T2.

本發明之實施例 14 （ d ） 係關於實施例14，其中G為含有兩個環烷基之5-9員碳環螺環，該等環烷基由一個共同螺碳原子連接，其中碳環螺環經0-2個T¹ 及0-1個T² 取代。 Embodiment 14 ( d ) of the present invention relates to Embodiment 14, wherein G is a 5-9 membered carbocyclic spiro ring containing two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic The spiro ring is substituted with 0-2 T ¹ and 0-1 T ² .

本發明之實施例 14 （ e ） 係關於實施例14，其中G為含有兩個具有至少一個雜原子之環狀基團的6-9員雜環螺環，其中兩個環狀基團由一個共同螺碳原子連接，其中雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代。 Embodiment 14 ( e ) of the present invention relates to embodiment 14, wherein G is a 6-9 membered heterocyclic spiro ring containing two cyclic groups having at least one heteroatom, wherein the two cyclic groups consist of a A common spiro carbon atom is attached, wherein the heterocyclic spiro ring system is substituted with 0-2 ^T5 , 0-1 ^T6 .

本發明之實施例 14 （ f ） 係關於實施例14，其中G係經0-2個T¹ 及0-1個T⁴ 取代之苯基。 Embodiment 14 ( f ) of the present invention relates to embodiment ¹⁴ , wherein G is phenyl substituted with 0-2 T1 and ^0-1 T4.

本發明之實施例 14 （ g ） 係關於實施例14，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基。 Embodiment 14 ( g ) of the present invention relates to embodiment ¹⁴ , wherein G is a ^4-6 membered heterocycloalkyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 14 （ h ） 係關於實施例14，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基。 Embodiment 14 ( h ) of the present invention relates to embodiment ¹⁴ , wherein G is a ^4-6 membered heterocycloalkenyl substituted with 0-2 T5 and 0-1 T6.

本發明之實施例 14 （ i ） 係關於實施例14，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環。 Embodiment 14 ( i ) of the present invention relates to embodiment 14, wherein G is a ^5-9 membered bridged heterocycle substituted with 0-2 T5 and 0-1 ^T6 .

本發明之實施例 14 （ j ） 係關於實施例14，其中G係經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 14 ( j ) of the present invention relates to embodiment ¹⁴ , wherein G is a ^5-6 membered heteroaryl substituted with 0-2 T5 and 0-1 T3.

本發明之實施例 14 （ k ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 。 Embodiment 14 ( k ) of the present invention relates to a compound such as Embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 14 （ l ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 14 ( l ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 14 （ m ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 14 ( m ) of the present invention relates to a compound as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T2 is -( ^CH2 _{) 0-1} -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 14 （ n ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 14 ( n ) of the present invention relates to a compound as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T2 is -( ^CH2 _{) 0-1} -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 14 （ o ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 14 ( o ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ .

本發明之實施例 14 （ p ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 14 ( p ) of the present invention relates to a compound as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T2 is -( ^CH2 _{) 0-1} -N( ^R9 )C(O) ^R8 .

本發明之實施例 14 （ q ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 。 Embodiment 14 ( q ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -N( ^R9 )C(O) ^OR9 .

本發明之實施例 14 （ r ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁸ )R⁹ 。 Embodiment 14 ( r ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ .

本發明之實施例 14 （ s ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 。 Embodiment 14 ( s ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ .

本發明之實施例 14 （ t ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 14 ( t ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)OR ⁹ .

本發明之實施例 14 （ u ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 14 ( u ) of the present invention relates to a compound such as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 14 （ v ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -C(O)H。 Embodiment 14 ( v ) of the present invention relates to a compound as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -C(O)H.

本發明之實施例 14 （ w ） 係關於如實施例14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 。 Embodiment 14 ( w ) of the present invention relates to a compound as embodiment 14, 14(a), 14(b), 14(c) or 14(d), wherein T ² is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 14 （ x ） 係關於如實施例5、14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基。 Embodiment 14 ( x ) of the present invention relates to a compound such as Embodiment 5, 14, 14(a), 14(b), 14(c) or 14(d), wherein T2 is optionally ^modified from 1-3 -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl substituted with Z ³ .

本發明之實施例 14 （ y ） 係關於如14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基。 Embodiment 14 ( y ) of the present invention relates to compounds such as 14, 14(a), 14(b), 14(c) or ¹⁴ ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 -(CH ₂ ) _0-1 -phenyl.

本發明之實施例 14 （ z ） 係關於如14、14（a）、14（b）、14（c）或14（d）之化合物，其中T² 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基。 Embodiment 14 ( z ) of the present invention relates to compounds such as 14, 14(a), 14(b), 14(c) or ¹⁴ ( ^d ) wherein T2 is optionally substituted with 1-3 Z5 The -(CH ₂ ) _0-1-5-6 membered heteroaryl.

本發明之實施例 14 （ aa ） 係關於如實施例14或14（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 。 Embodiment 14 ( aa ) of the present invention relates to a compound as embodiment 14 or ¹⁴ (j), wherein T3 is -( _CH2 ) _0-2 -C(O)N( ^R8 ) ^R9 .

本發明之實施例 14 （ ab ） 係關於如實施例14或14（j）之化合物，其中T³ 為-(CH₂ )_0-2 -N(R⁸ )R⁹ ，其限制條件為當T³ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 14 ( ab ) of the present invention relates to the compound as embodiment 14 or 14(j), wherein T ³ is -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , with the limitation that when T When ³ is attached to the heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 14 （ ac ） 係關於如實施例14或14（j）之化合物，其中T³ 為-(CH₂ )_0-2 -C(O)OR⁹ 。 Embodiment 14 ( ac ) of the present invention relates to a compound as embodiment 14 or ¹⁴ (j), wherein T3 is -( _CH2 ) _0-2 -C(O) ^OR9 .

本發明之實施例 14 （ ad ） 係關於如實施例14或14（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基。 Embodiment 14 ( ad ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T3 is ^- ( _CH2 ) optionally substituted with ^1-3 Z5 and ^0-1 Z1 _{0-2 -} C3 _- C6cycloalkyl.

本發明之實施例 14 （ ae ） 係關於如實施例14或14（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-6員雜環烷基，其限制條件為當T³ 連接至G之雜原子時，G不連接至5-6員雜環烷基之氧原子或氮原子。 Embodiment 14 ( ae ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-6 membered heterocycloalkyl with the proviso that when T3 is attached to a heteroatom ^of G, G is not attached to an oxygen or nitrogen atom of the 5-6 membered heterocycloalkyl.

本發明之實施例 14 （ af ） 係關於如實施例14或14（j）之化合物，其中T³ 為視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基。 Embodiment 14 ( af ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T3 is optionally via ⁴ -chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl.

本發明之實施例 14 （ ag ） 係關於如實施例14或14（j）之化合物，其中T³ 為視情況經1-3個Z⁵ 及0-1個Z¹ 取代之-(CH₂ )_0-2 -5-9員橋接碳環。 Embodiment 14 ( ag ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T3 is ^- ( _CH2 ) optionally substituted by ^1-3 Z5 and ^0-1 Z1 _0-2-5-9 member bridged carbon rings.

本發明之實施例 14 （ ah ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 C(O)OR⁹ 。 Embodiment 14 ( ah ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T4 is ^- ( _CH2 ) _0-1C (O) ^OR9 .

本發明之實施例 14 （ ai ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 。 Embodiment 14 ( ai ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ .

本發明之實施例 14 （ aj ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R。 Embodiment 14 ( aj ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T4 is ^- ( _CH2 ) _0-1 -N( ^R9 )SO2 _- R.

本發明之實施例 14 （ ak ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 14 ( ak ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 14 （ al ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 14 ( a1 ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T ⁴ is -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例14（am）係關於如實施例14或14（j）之化合物，其中T⁴ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 。Embodiment 14(am) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T ⁴ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 14 （ an ） 係關於如實施例14或14（j）之化合物，其中T⁴ 為N(R^a )₂ 。 Embodiment 14 ( an ) of the present invention relates to a compound as embodiment 14 or 14(j), wherein T ⁴ is N(R ^a ) ₂ .

本發明之實施例 14 （ ao ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ -R⁷ 。 Embodiment 14 ( ao ) of the present invention relates to a compound such as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )SO ₂ -R ⁷ .

本發明之實施例 14 （ ap ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ -R⁷ 。 Embodiment 14 ( ap ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ -R ⁷ .

本發明之實施例 14 （ aq ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 。 Embodiment 14 ( aq ) of the present invention relates to a compound such as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -SO ₂ N(R ⁸ )R ⁹ .

本發明之實施例 14 （ ar ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 。其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )SO₂ N(R⁸ )R⁹ 。 Embodiment 14 ( ar ) of the present invention relates to a compound such as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ . The limitation is that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )SO2N ₍ ^R8 ) ^R9 .

本發明之實施例 14 （ as ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)N(R⁸ )R⁹ 。 Embodiment 14 ( as ) of the present invention relates to a compound such as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)N(R ⁸ ) ^R9 .

本發明之實施例 14 （ at ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R⁸ 。 Embodiment 14 ( at ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -N( ^R9 )C(O) ^R8 with the proviso that when ^T6 is attached to a heteroatom of G, G is not attached to -N( ^R9 )C(O) ^R8 .

本發明之實施例 14 （ au ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)OR⁹ 。 Embodiment 14 ( au ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁹ )C(O)OR ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)OR ⁹ .

本發明之實施例 14 （ av ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁸ )R⁹ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁸ )R⁹ 。 Embodiment 14 ( av ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -N(R ⁸ )R ⁹ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁸ )R ⁹ .

本發明之實施例 14 （ aw ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 。 Embodiment 14 ( aw ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)-N(R ⁸ )R ⁹ .

本發明之實施例 14 （ ax ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)OR⁹ 。 Embodiment 14 ( ax ) of the present invention relates to a compound such as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)OR ⁹ .

本發明之實施例 14 （ ay ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -C(O)R¹⁰ 。 Embodiment 14 ( ay ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -( _CH2 ) _0-1 -C(O)R ¹⁰ .

本發明之實施例 14 （ az ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ ，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至-N(R⁹ )C(O)R¹⁰ 。 Embodiment 14 ( az ) of the present invention relates to a compound such as Embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein T ⁶ is -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to -N(R ⁹ )C(O)R ¹⁰ .

本發明之實施例 14 （ ba ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為-N(H)C(H)C=O，其限制條件為T⁶ 不連接至G之雜原子。 Embodiment 14 ( ba ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is -N(H)C(H )C=O, with the proviso that ^T6 is not attached to a G heteroatom.

本發明之實施例 14 （ bb ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基。 Embodiment 14 ( bb ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is optionally through 1-4 Z ³ -substituted -(CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl.

本發明之實施例 14 （ bc ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 14 ( bc ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is optionally via 1-4 Z ³ -substituted -(CH ₂ ) _0-1-5-6 membered heterocycloalkyl, with the proviso that when T ⁶ is attached to a heteroatom of G, G is not attached to a heteroatom of a 5-6 membered heteroaryl .

本發明之實施例 14 （ bd ） 係關於如實施例14、14（e）、14（g）、14（h）或14（i）之化合物，其中T⁶ 為視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，其限制條件為當T⁶ 連接至G之雜原子時，G不連接至5-6員雜芳基之雜原子。 Embodiment 14 ( bd ) of the present invention relates to a compound as embodiment 14, 14(e), 14(g), 14(h) or 14(i), wherein ^T6 is optionally via 1-3 Z ⁵ -substituted -( _CH2 ) _0-1-5-6 membered heteroaryl, with the proviso that when ^T6 is attached to the heteroatom of G, G is not attached to the heteroatom of the 5-6 membered heteroaryl.

實施例 14 （ be ） 係關於實施例14、14（a）、14（b）、14（c）、14（d）、14（e）、14（f）、14（g）、14（h）、14（i）、14（j）、14（k）、14（l）、14（m）、14（n）、14（o）、14（p）、14（q）、14（r）、14（s）、14（t）、14（u）、14（v）、14（w）、14（x）、14（y）、14（z）、14（aa）、14（ab）、14（ac）、14（ad）、14（ae）、14（af）、14（ag）、14（ah）、14（ai）、14（aj）、14（ak）、14（al）、14（am）、14（an）、14（ao）、14（ap）、14（aq）、14（ar）、14（as）、14（at）、14（au）、14（av）、14（aw）、14（ax）、14（ay）、14（az）、14（ba）、14（bb）、14（bc）或14（bd）中之任一者，其中R² 為Cl。 Example 14 ( be ) relates to Examples 14, 14(a), 14(b), 14(c), 14(d), 14(e), 14(f), 14(g), 14(h ), 14(i), 14(j), 14(k), 14(l), 14(m), 14(n), 14(o), 14(p), 14(q), 14(r ), 14(s), 14(t), 14(u), 14(v), 14(w), 14(x), 14(y), 14(z), 14(aa), 14(ab ), 14(ac), 14(ad), 14(ae), 14(af), 14(ag), 14(ah), 14(ai), 14(aj), 14(ak), 14(al ), 14(am), 14(an), 14(ao), 14(ap), 14(aq), 14(ar), 14(as), 14(at), 14(au), 14(av) ), 14(aw), 14(ax), 14(ay), 14(az), 14(ba), 14(bb), 14(bc) or 14(bd), where R ² is Cl.

實施例 14 （ bf ） 係關於實施例14、14（a）、14（b）、14（c）、14（d）、14（e）、14（f）、14（g）、14（h）、14（i）、14（j）、14（k）、14（l）、14（m）、14（n）、14（o）、14（p）、14（q）、14（r）、14（s）、14（t）、14（u）、14（v）、14（w）、14（x）、14（y）、14（z）、14（aa）、14（ab）、14（ac）、14（ad）、14（ae）、14（af）、14（ag）、14（ah）、14（ai）、14（aj）、14（ak）、14（al）、14（am）、14（an）、14（ao）、14（ap）、14（aq）、14（ar）、14（as）、14（at）、14（au）、14（av）、14（aw）、14（ax）、14（ay）、14（az）、14（ba）、14（bb）、14（bc）或14（bd）中之任一者，其中R² 為CN。 Example 14 ( bf ) relates to Examples 14, 14(a), 14(b), 14(c), 14(d), 14(e), 14(f), 14(g), 14(h) ), 14(i), 14(j), 14(k), 14(l), 14(m), 14(n), 14(o), 14(p), 14(q), 14(r ), 14(s), 14(t), 14(u), 14(v), 14(w), 14(x), 14(y), 14(z), 14(aa), 14(ab ), 14(ac), 14(ad), 14(ae), 14(af), 14(ag), 14(ah), 14(ai), 14(aj), 14(ak), 14(al ), 14(am), 14(an), 14(ao), 14(ap), 14(aq), 14(ar), 14(as), 14(at), 14(au), 14(av) ), 14(aw), 14(ax), 14(ay), 14(az), 14(ba), 14(bb), 14(bc) or 14(bd), where R ² for CN.

實施例 15 係關於如實施例12之化合物，其具有式IV（a）、IV（b）、IV（c）、IV（d）、IV（e）、IV（f）中之一者，或其醫藥學上可接受之鹽，或式IV（a）、IV（b）、IV（c）、IV（d）、IV（e）、IV（f）中之任一子實施例，或其醫藥學上可接受之鹽。 Embodiment 15 relates to a compound as embodiment 12 having one of formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), or A pharmaceutically acceptable salt thereof, or any sub-embodiment of formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), or its A pharmaceutically acceptable salt.

實施例 16 係關於如實施例13之化合物，其具有式V（a）、V（b）、V（c）、V（d）、V（e）、V（f）、V（g）、V（h）、V（i）、V（j）、V（k）、V（l）、V（m）、V（n）、V（o）、V（p）、V（q）、V （r）、V（s）、V（t）、V（u）、V（v）、V（w）、V（af）、V（ag）、V（ah）、V（ai）、V（aj）、V（ak）、V（al）、V（am）、V（an）、V（ao）、V（ap）、V（aq）、V（ar）、V（as）、V （at）、V（au）、V（av）、V（aw）、V（ay）、V（az）、V（ba）、V（bb）中之一者，或其醫藥學上可接受之鹽，或式V（a）、V（b）、V（c）、V（d）、V（e）、V（f）、V（g）、V（h）、V（i）、V（j）、V（k）、V（l）、V（m）、V（n）、V（o）、V（p）、V（q）、V（r）、V（s）、V（t）、V（u）、V（v）、V（w）、V（af）、V（ag）、V（ah）、V（ai）、V（aj）、V（ak）、V（al）、V（am）、V（an）、V（ao）、V（ap）、V（aq）、V（ar）、V（as）、V（at）、V（au）、V（av）、V（aw）、V（ay）、V（az）、V（ba）、V（bb）中之任一子實施例，或其醫藥學上可接受之鹽。 Embodiment 16 relates to a compound as embodiment 13 having formula V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i), V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s), V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak), V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), One of V(at), V(au), V(av), V(aw), V(ay), V(az), V(ba), V(bb), or its pharmaceutically acceptable Accepted salt, or formula V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i) , V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s) , V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak) , V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), V(at), V(au) , V(av), V(aw), V(ay), V(az), V(ba), V(bb), or a pharmaceutically acceptable salt thereof.

實施例 17 係關於如實施例14之化合物，其具有式VI（a）、VI（b）、VI（c）、VI（d）、VI（e）、VI（f）、VI（g）、VI（h）、VI（i）、VI（j）、VI（k）、VI（l）、VI（m）、VO（n）、VI（o）中之一者，或其醫藥學上可接受之鹽，或式VI（a）、VI（b）、VI（c）、VI（d）、VI（e）、VI（f）、VI（g）、VI（h）、VI（i）、VI（j）、VI（k）、VI（l）、VI（m）、VO（n）、VI（o）中之任一子實施例，或其醫藥學上可接受之鹽。 Example 17 relates to a compound as Example 14 having formula VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), One of VI(h), VI(i), VI(j), VI(k), VI(l), VI(m), VO(n), VI(o), or its pharmaceutically acceptable Accepted salt, or formula VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), VI(h), VI(i) , VI(j), VI(k), VI(l), VI(m), VO(n), VI(o), or a pharmaceutically acceptable salt thereof.

實施例 18 係關於如前述實施例中任一項之化合物，其中G 為以下基團中之一者： (a)      經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (b)      經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (c)      6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代； (d)      經0-2個T¹ 及0-1個T⁴ 取代之苯基； (e)      經0-2個T⁵ 及0-1個T⁶ 取代之5-6員雜環烷基； (f)       經0-2個T⁵ 及0-1個T⁶ 取代之5-6員雜環烯基； (g)      經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (h)      經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。 Embodiment 18 relates to a compound as in any one of the preceding embodiments, wherein G is one of the following groups: (a) C3 _- C substituted with ^0-2 T1 and ^0-1 T2 ₆ -cycloalkyl; (b) C ₃ -C ₆ cycloalkenyl substituted with 0-2 T ¹ and 0-1 T ² ; (c) 6-9 membered heterocyclic spiro ring, which contains two A cyclic group of at least one heteroatom, wherein the two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted with 0-2 T ⁵ , 0-1 T ⁶ ; (d) phenyl substituted with 0-2 T ¹ and 0-1 T ⁴ ; (e) 5-6 membered heterocycloalkyl substituted with 0-2 T ⁵ and 0-1 T ⁶ ; (f) 5-6 membered heterocycloalkenyl substituted with 0-2 T ⁵ and 0-1 T ⁶ ; (g) 5-9 substituted with 0-2 T ⁵ and 0-1 T ⁶ or (h ^{) 5-6} membered heteroaryl substituted with 0-2 T5 and 0-1 T3.

實施例 19 係關於如實施例16之化合物，其中G係吡唑基、異

唑基、吲哚基、1,2,3-***基、咪唑基、噻唑基或吡咯基，其中之每一者係經0-2個T⁵ 及0-1個T³ 取代。實施例 19 之子實施例 Embodiment 19 relates to the compound of embodiment 16, wherein G is pyrazolyl, iso

azolyl, indolyl, 1,2,3-triazolyl, imidazolyl, thiazolyl or pyrrolyl, each ^of which is substituted with 0-2 ^T5 and 0-1 T3. Sub-Example of Example 19

實施例19（a）係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之吡唑基。Embodiment 19(a) relates to a compound as Embodiment ¹⁹ wherein G is pyrazolyl substituted with 0-2 ^T5 and 0-1 T3.

實施例 19 （ b ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之異

唑基。 Embodiment 19 ( b ) relates to a compound as in embodiment 19, wherein G is isosubstituted by 0-2 T ⁵ and 0-1 T ³

azolyl.

實施例 19 （ c ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之吲哚基。 Embodiment 19 ( c ) relates to a compound as Embodiment ¹⁹ , wherein G is indolyl substituted with 0-2 ^T5 and 0-1 T3.

實施例 19 （ d ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之1,2,3-***基。 Embodiment 19 ( d ) relates to a compound as embodiment ¹⁹ , wherein G is 1,2,3 ^- triazolyl substituted with 0-2 T5 and 0-1 T3.

實施例 19 （ e ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之咪唑基。 Embodiment 19 ( e ) relates to a compound as embodiment ¹⁹ , wherein G is imidazolyl substituted with 0-2 ^T5 and 0-1 T3.

實施例 19 （ f ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之噻唑基。 Embodiment 19 ( f ) relates to a compound as embodiment ¹⁹ , wherein G is thiazolyl substituted with 0-2 ^T5 and 0-1 T3.

實施例 19 （ g ） 係關於如實施例19之化合物，其中G係經0-2個T⁵ 及0-1個T³ 取代之吡咯基。 Embodiment 19 ( g ) relates to a compound as embodiment ¹⁹ , wherein G is pyrrolyl substituted with 0-2 ^T5 and 0-1 T3.

實施例 20 係關於如實施例16之化合物，其中G為2,5-二氫吡咯基或3,6-二氫哌喃基，其中之每一者係經0-2個T⁵ 及0-1個T⁶ 取代。實施例 20 之子實施例 Embodiment 20 relates to a compound as embodiment 16, wherein G is ^2,5 -dihydropyrrolyl or 3,6-dihydropyranyl, each of which is via 0-2 T and 0- 1 T ⁶ substitution. Sub-Example of Example 20

實施例 20 （ a ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之哌

基。 Embodiment 20 ( a ) relates to a compound as embodiment 20, wherein G is piperidine substituted with 0-2 T ⁵ and 0-1 T ⁶

base.

實施例 20 （ b ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之哌啶。 Embodiment 20 ( b ) relates to a compound as embodiment ²⁰ , wherein G is piperidine substituted with 0-2 T5 and 0-1 ^T6 .

實施例 20 （ c ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之吡咯啶。 Embodiment 20 ( c ) relates to a compound as embodiment ²⁰ , wherein G is pyrrolidine substituted with 0-2 T5 and 0-1 ^T6 .

實施例 20 （ d ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之四氫哌喃。 Embodiment 20 ( d ) relates to a compound as embodiment ²⁰ , wherein G is tetrahydropyran substituted with 0-2 T5 and 0-1 ^T6 .

實施例 20 （ e ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之

啉基。 Embodiment 20 ( e ) relates to the compound of embodiment 20, wherein G is substituted by 0-2 T ⁵ and 0-1 T ⁶

Linyl.

實施例 20 （ f ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之1,2,3,6-四氫吡啶基。 Embodiment 20 ( f ) relates to a compound as embodiment 20, wherein G is 1,2,3,6 ^- tetrahydropyridyl substituted with 0-2 T5 and 0-1 ^T6 .

實施例 20 （ g ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之2,5-二氫吡咯基。 Embodiment 20 ( g ) relates to a compound as embodiment 20, wherein G is ^2,5 -dihydropyrrolyl substituted with 0-2 T5 and 0-1 ^T6 .

實施例 20 （ h ） 係關於如實施例20之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之3,6-二氫哌喃基。 Embodiment 20 ( h ) relates to a compound as embodiment 20, wherein G is 3,6 ^- dihydropyranyl substituted with 0-2 T5 and 0-1 ^T6 .

實施例 21 係關於如實施例 16 之化合物，其中G為(1R,5S)-3,8-二氮雜二環[3.2.1]辛基、(1R,5S)-3-氮雜二環[3.2.1]辛基或(1R,5S)-8-氮雜二環[3.2.1]辛基，其中之每一者係經0-2個T⁵ 及0-1個T⁶ 取代。實施例 21 之子實施例 Embodiment 21 relates to a compound as embodiment 16 , wherein G is (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3-azabicyclo [3.2.1] Octyl or (1R,5S)-8 ^- azabicyclo[3.2.1]octyl, each of which is substituted with 0-2 T5 and 0-1 ^T6 . Sub-Example of Example 21

實施例 21 （ a ） 係關於如實施例21之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之(1R,5S)-3,8-二氮雜二環[3.2.1]辛基。 Embodiment 21 ( a ) relates to the compound of embodiment 21, wherein G is (1R,5S) ^{-3,8 -} diazabicyclo[ 3.2.1] Octyl.

實施例 21 （ b ） 係關於如實施例21之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之(1R,5S)-3-氮雜二環[3.2.1]辛基。 Embodiment 21 ( b ) relates to a compound as embodiment 21, wherein G is (1R,5S)-3-azabicyclo[3.2.1 substituted with 0-2 T ⁵ and 0-1 T ⁶ ] Octy.

實施例 21 （ c ） 係關於如實施例21之化合物，其中G係經0-2個T⁵ 及0-1個T⁶ 取代之(1R,5S)-8-氮雜二環[3.2.1]辛基。 Embodiment 21 ( c ) relates to a compound as embodiment 21, wherein G is (1R,5S)-8-azabicyclo[3.2.1 substituted with 0-2 T ⁵ and 0-1 T ⁶ ] Octy.

實施例 22 係關於如實施例 16 之化合物，其中G為環己基、環戊基、環己烯基、環戊烯基，其中之每一者係經0-2個T¹ 及0-1個T² 取代。實施例 22 之子實施例 Embodiment 22 relates to a compound as embodiment 16 , wherein G is cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, each of which is separated by 0-2 T and ^0-1 T ² substituted. Sub-Example of Example 22

實施例 22 （ a ） 係關於如實施例 22 之化合物，其中G係經0-2個T¹ 及0-1個T² 取代之環己基。 Embodiment 22 ( a ) relates to a compound as Embodiment 22 , wherein G is cyclohexyl substituted with 0-2 T ¹ and 0-1 T ² .

實施例 22 （ b ） 係關於如實施例 22 之化合物，其中G係經0-2個T¹ 及0-1個T² 取代之環戊基。 Embodiment 22 ( b ) relates to a compound as embodiment 22 , wherein G is cyclopentyl substituted with 0-2 T ¹ and 0-1 T ² .

實施例 22 （ c ） 係關於如實施例 22 之化合物，其中G係經0-2個T¹ 及0-1個T² 取代之環己烯基。 Embodiment 22 ( c ) relates to a compound as Embodiment 22 , wherein G is cyclohexenyl substituted with ^0-2 T1 and ^0-1 T2.

實施例 22 （ d ） 係關於如實施例 22 之化合物，其中G係經0-2個T¹ 及0-1個T² 取代之環戊烯基。 Embodiment 22 ( d ) relates to a compound as embodiment 22 , wherein G is cyclopentenyl substituted with ^0-2 T1 and ^0-1 T2.

實施例 23 係關於如實施例 1 至 17 中任一項之化合物，其中T³ 為-CH₂ C(O)N(H)環丙基、-CH₂ C(O)N(H)CH₃ 、-CH₂ -COOH、氧雜環丁烷基、-(CH₂ )_0-2 環丙基、-(CH₂ )_0-2 環丁基、-(CH₂ )_0-2 -四氫哌喃、-(CH₂ )_0-2 -四氫呋喃、-(CH₂ )_0-2 吖呾基、-(CH₂ )_0-2 吡咯啶基，或-(CH₂ )_0-2

啉基。 Embodiment 23 relates to a compound as any one of embodiments 1 to 17 , wherein T3 is ^-CH2C (O)N(H)cyclopropyl, _-CH2C (O)N(H _{) CH3} , -CH ₂ -COOH, oxetanyl, -(CH ₂ ) _0-2 cyclopropyl, -(CH ₂ ) _0-2 cyclobutyl, -(CH ₂ ) _0-2 -tetrahydropiperidine furan, -(CH ₂ ) _0-2 -tetrahydrofuran, -(CH ₂ ) _0-2 acryl, -(CH ₂ ) _0-2 pyrrolidinyl, or -(CH ₂ ) _0-2

Linyl.

實施例 24 係關於如實施例 1 至 17 中任一項之化合物，其中G 為下式中之一者：

. Embodiment 24 relates to a compound as any one of embodiments 1 to 17 , wherein G is one of the following formulae:

.

實施例 25 係關於如實施例 1 至 17 中任一項之化合物，其中G 為下式中之一者：

. 各T^1a 獨立地為F、Cl或CH₃ ；且 各T^5a 獨立地為F、Cl或CH₃ 。 Embodiment 25 relates to a compound as any one of embodiments 1 to 17 , wherein G is one of the following formulae:

. each T ^1a is independently F, CI or CH ₃ ; and each T ^5a is independently F, CI or CH ₃ .

實施例 26 係關於如實施例 25 之化合物，其中G 為式（a）、（b）、（c）、（d）、（e）、（f）、（g）或（h）中之一者， Embodiment 26 relates to a compound as embodiment 25 , wherein G is one of formula (a), (b), (c), (d), (e), (f), (g) or (h) By,

實施例 27 係關於如實施例 25 之化合物，其中G 為式（i）、（j）、（k）、（l）、（m）、（n）、（o）、（p）、（q）、（r）、（s）、（t）、（u）、（v）、（w）、（x）、（y）、（z）、（aa）、（ab）、（ac）或（ad）中之一者。 Embodiment 27 relates to a compound as embodiment 25 , wherein G is of formula (i), (j), (k), (l), (m), (n), (o), (p), (q ), (r), (s), (t), (u), (v), (w), (x), (y), (z), (aa), (ab), (ac) or one of (ad).

實施例 28 係關於如實施例 25 之化合物，其中G 為式（ae）、（af）、（ag）、（ah）、（ai）、（aj）、（ak）、（al）、（am）、（an）、（ao）、（ap）或（aq）中之一者。 Embodiment 28 relates to a compound as embodiment 25 , wherein G is of formula (ae), (af), (ag), (ah), (ai), (aj), (ak), (al), (am ), (an), (ao), (ap) or (aq).

實施例 29 係關於如實施例 25 之化合物，其中G 為式（ar）或（as）中之一者。 Embodiment 29 relates to a compound as embodiment 25 , wherein G is one of formula (ar) or (as).

實施例 30 係關於如實施例 25 之化合物，其中G 為式（at）或（au）中之一者。 Embodiment 30 relates to a compound as embodiment 25 , wherein G is one of formula (at) or (au).

實施例 31 係關於如實施例 25 之化合物，其中G 為式（av）、（aw）、（ax）、（ay）或（az）中之一者。 Embodiment 31 relates to a compound as embodiment 25 , wherein G is one of formula (av), (aw), (ax), (ay) or (az).

實施例 32 係關於如實施例 1 至 25 或27 中任一項之化合物，其中T⁶ 氧雜環丁烷基亞甲基、-C(O)CH₂ OH、-C(O)OH、-SO₂ CH₃ 、-C(O)環丙基、-C(O)CH₃ 、-N(H)SO₂ -環丙基、-N(H)C(O)環丙基、-SO₂ N(H)CH₂ CH₂ CH₃ 、-SO₂ NH環丙基或-SO₂ CH₂ CH₂ CH₃ 。 Embodiment 32 relates to a compound as any one of embodiments 1 to 25 or 27 , wherein ^T6 oxetanylmethylene, -C(O)CH2OH, _-C (O)OH, - SO ₂ CH ₃ , -C(O)cyclopropyl, -C(O)CH ₃ , -N(H)SO ₂ -cyclopropyl, -N(H)C(O)cyclopropyl, -SO _{2 N ( H ) CH2CH2CH3} , _{-SO2NHcyclopropyl or -SO2CH2CH2CH3} .

實施例 33 係關於如實施例 1 至 25 、27 或29 中任一項之化合物，其中T⁵ 係F、Cl、CH₂ Cl、CH₂ F、CH₃ 、-CH₂ CH₃ 、-CH(CH₃ )₂ 、CH₂ OH、-CH₂ CH₂ OH、-CH₂ C(CH₃ )₂ OH、-CH(CH₂ OH)₂ 、-CH₂ CH(OH)CF₃ 、CH₂ CF₃ 、CN、-CH₂ CN、-OCH₃ 、-CH₂ OCH₃ 、-CHF₂ 、-CH₂ CHF₂ 、-CH₂ CH(OH)CH₂ CH₂ Cl、-CH(CH₂ OH)CH₂ Cl、-CH(CH₂ OH)CH₂ I，或-CH₂ C(CH₃ )(CH₂ OH)CH₂ Cl。 Embodiment 33 relates to a compound as any one of embodiments 1 to 25 , 27 or 29 , wherein ^T5 is F, _Cl , _CH2Cl , _CH2F , _CH3 , -CH2CH3, -CH ₍ CH ₃ ) ₂ , CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ C(CH ₃ ) ₂ OH, -CH(CH ₂ OH) ₂ , -CH ₂ CH(OH)CF ₃ , CH ₂ CF ₃ , CN, _-CH2CN , _-OCH3 , _-CH2OCH3 , _-CHF2 , _-CH2CHF2 , -CH2CH ₍ OH _{) CH2CH2Cl} , -CH _{( CH2OH ) CH2} Cl, -CH(CH2OH)CH2I, or _-CH2C ( _{CH3 ) (} CH2OH _{) CH2Cl} .

實施例 34 係關於如實施例 1 至 25 中任一項之化合物，其中Z⁵ 為CH₃ 、F、Cl、CN、-CH₂ CN、-CH₂ CH₃ 或OH。 Embodiment 34 is directed to a compound as in any one of embodiments 1 to 25 , wherein ^Z5 is _CH3 , F, _Cl , CN, _-CH2CN , _-CH2CH3 or OH.

實施例 35 係關於選自表1之如實施例1之化合物或其醫藥學上可接受之鹽。 Example 35 relates to a compound selected from Table 1 as Example 1 or a pharmaceutically acceptable salt thereof.

此外，該等式意欲涵蓋所鑑別結構之水合或溶劑化以及非水合或非溶劑化形式。舉例而言，所指示之化合物包括水合及非水合形式。溶劑合物之其他實例包括結構與適合的溶劑（諸如異丙醇、乙醇、甲醇、二甲亞碸、乙酸乙酯、乙酸或乙醇胺）之組合。III. 調配物及投與 Furthermore, the equations are intended to encompass hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures. For example, the indicated compounds include hydrated and non-hydrated forms. Other examples of solvates include structures in combination with a suitable solvent such as isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, or ethanolamine. III. Formulations and Administration

本發明之實施例 36 係關於一種醫藥組合物，其包含本發明之一個實施例中之化合物（如實施例1至35中任一項（包括其任何子實施例）之化合物）及醫藥學上可接受之載劑。 Embodiment 36 of the present invention relates to a pharmaceutical composition comprising a compound of one embodiment of the present invention (such as a compound of any one of Embodiments 1 to 35 (including any sub-embodiments thereof)) and pharmaceutically acceptable carrier.

本發明之實施例 37 係關於如實施例36之醫藥組合物，其進一步包含第二藥劑。 Embodiment 37 of the present invention relates to the pharmaceutical composition of embodiment 36, which further comprises a second agent.

適合的劑型部分視投與用途或途徑而定，例如口服、經皮、經黏膜、吸入劑或藉由注射（非經腸）。此類劑型應使得化合物到達靶細胞。其他因素為此項技術中熟知，且包括考慮因素，諸如毒性及阻礙化合物或組合物發揮其作用之劑型。技術及調配物通常可見於《藥劑學之科學及實踐（The Science and Practice of Pharmacy）》, 第21版, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005（以引用之方式併入本文中）中。Suitable dosage forms depend in part on the purpose or route of administration, eg, oral, transdermal, transmucosal, inhalation, or by injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that hinder the compound or composition from exerting its effect. Techniques and formulations are generally found in The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference) .

本發明之化合物（亦即，實施例1-36（包括其任何子實施例）中所描述之化合物中之任一者）可以調配為醫藥學上可接受之鹽。The compounds of the invention (ie, any of the compounds described in Examples 1-36 (including any sub-embodiments thereof)) can be formulated as pharmaceutically acceptable salts.

載劑或賦形劑可以用於產生組合物。可以選擇載劑或賦形劑以促進化合物之投與。載劑之實例包括碳酸鈣；磷酸鈣；各種糖，諸如乳糖、葡萄糖或蔗糖；或澱粉類型；纖維素衍生物；明膠；植物油；聚乙二醇及生理學上相容之溶劑。生理學上相容之溶劑之實例包括注射用水（WFI）、生理食鹽水溶液及右旋糖之無菌溶液。Carriers or excipients can be used to produce the compositions. The carrier or excipient can be selected to facilitate administration of the compound. Examples of carriers include calcium carbonate; calcium phosphate; various sugars such as lactose, glucose or sucrose; or starch types; cellulose derivatives; gelatin; vegetable oils; polyethylene glycols and physiologically compatible solvents. Examples of physiologically compatible solvents include water for injection (WFI), physiological saline solution, and sterile solutions of dextrose.

化合物可以藉由不同途徑投與，包括靜脈內、腹膜內、皮下、肌內、經口、經黏膜、經直腸、經皮或吸入劑。在一些實施例中，可以藉由口服投與來投與化合物。對於口服投與，舉例而言，化合物可以調配為習知口服劑型，諸如膠囊、錠劑及液體製劑，諸如糖漿、酏劑及濃縮滴劑。The compounds can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalation. In some embodiments, the compounds can be administered by oral administration. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms, such as capsules, lozenges, and liquids, such as syrups, elixirs, and concentrated drops.

對於吸入劑，本發明之化合物可調配為乾燥粉末或適合的溶液、懸浮液或噴霧劑。粉末及溶液可藉由此項技術中已知之適合的添加劑來調配。舉例而言，粉末可包括適合粉末基質，諸如乳糖或澱粉，且溶液可包含丙二醇、無菌水、乙醇、氯化鈉及其他添加劑，諸如酸、鹼及緩衝鹽。此類溶液或懸浮液可藉由吸入，經由噴霧器、泵、霧化器或噴灑器及其類似物投與。本發明之化合物亦可與其他吸入療法組合使用，例如皮質類固醇，諸如丙酸氟替卡松（fluticasone proprionate）、二丙酸倍氯米松（beclomethasone dipropionate）、曲安奈德（triamcinolone acetonide）、布***（budesonide）及糠酸莫米松（mometasone furoate）；β促效劑，諸如沙丁胺醇（albuterol）、沙美特羅（salmeterol）及福莫特羅（formoterol）；抗膽鹼激導性藥劑，諸如異丙托溴銨（ipratroprium bromide）或噻托銨（tiotropium）；血管擴張劑，諸如曲前列環素（treprostinal）及伊洛前列素（iloprost）；酶，諸如DNAase；治療蛋白；免疫球蛋白抗體；寡核苷酸，諸如單或雙股DNA或RNA、siRNA；抗生素，諸如托普黴素（tobramycin）；蕈毒鹼受體拮抗劑；白三烯拮抗劑；細胞介素拮抗劑；蛋白酶抑制劑；色甘酸鈉；尼德瑞鈉（nedocril sodium）及色苷酸鈉。For inhalation, the compounds of the present invention can be formulated as dry powders or as suitable solutions, suspensions or sprays. Powders and solutions can be formulated with suitable additives known in the art. For example, powders can include suitable powder bases such as lactose or starch, and solutions can include propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, bases, and buffer salts. Such solutions or suspensions can be administered by inhalation, via a nebulizer, pump, atomizer or spray, and the like. The compounds of the present invention may also be used in combination with other inhaled therapies, such as corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide ) and mometasone furoate; beta agonists such as albuterol, salmeterol and formoterol; anticholinergic agents such as ipratropium bromide ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides Acids such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; interferon antagonists; protease inhibitors; cromolyn Sodium; nedocril sodium and cromolyn sodium.

經口使用之醫藥製劑可以例如藉由組合活性化合物與固體賦形劑，視情況研磨所得混合物且視需要在添加適合的助劑之後處理顆粒之混合物以獲得錠劑或糖衣藥丸核心來獲得。適合的賦形劑尤其為填充劑，諸如糖，包括乳糖、蔗糖、甘露糖醇或山梨糖醇；纖維素製劑，例如玉米澱粉、小麥澱粉、大米澱粉、馬鈴薯澱粉、明膠、黃蓍膠、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉（CMC）及/或聚乙烯吡咯啶酮（PVP：普維酮（povidone））。若需要，則可添加崩解劑，諸如交聯聚乙烯吡咯啶酮、瓊脂或海藻酸或其鹽，諸如海藻酸鈉。Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain dragees or dragee cores. Suitable excipients are especially fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl methacrylate cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC) and/or polyvinylpyrrolidone (PVP: povidone). If desired, a disintegrant such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

糖衣藥丸核心具有適合的包衣。出於此目的，可使用濃縮的糖溶液，其可視情況含有例如***膠、滑石、聚乙烯基吡咯啶酮、卡波莫凝膠（carbopol gel）、聚乙二醇（PEG）及/或二氧化鈦、塗漆溶液及適合的有機溶劑或溶劑混合物。可向錠劑或糖衣藥丸包衣中添加染料或顏料以鑑別或表徵活性化合物劑量之不同組合。Dragee cores have suitable coatings. For this purpose, concentrated sugar solutions may be used, which optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and/or titanium dioxide , paint solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the dragee or dragee coatings for identification or to characterize different combinations of active compound doses.

可以經口使用之醫藥製劑包括由明膠製成之配合***膠囊（「膠囊錠」）以及由明膠及塑化劑（諸如甘油或山梨糖醇）製成之密封軟膠囊。配合***型膠囊可以含有活性成分，其與諸如乳糖之填充劑、諸如澱粉之黏合劑及/或諸如滑石或硬脂酸鎂的潤滑劑以及視情況選用之穩定劑混合。在軟膠囊中，活性化合物可溶解或懸浮於諸如脂肪油、液體石蠟或液體聚乙二醇（PEG）之適合的液體中。此外，可添加穩定劑。Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("capsules"), as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol (PEG). In addition, stabilizers can be added.

或者，可使用注射（非經腸投與），例如肌肉內、靜脈內、腹膜內及/或皮下。對於注射，在無菌液體溶液中（諸如在生理學上相容之緩衝液或溶液，諸如生理食鹽水溶液、漢克氏溶液（Hank's solution）或林格氏溶液（Ringer's solution）中）調配本發明之化合物。此外，化合物可經調配呈固體形式，且在即將使用之前再溶解或懸浮。亦可以產生凍乾形式。Alternatively, injection (parenteral administration), eg, intramuscular, intravenous, intraperitoneal and/or subcutaneous, may be used. For injection, formulations of the invention are formulated in sterile liquid solutions such as physiologically compatible buffers or solutions such as physiological saline solution, Hank's solution or Ringer's solution compound. Additionally, the compounds can be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

投與亦可以藉由經黏膜、局部、經皮或吸入劑方式。對於經黏膜、局部或經皮投與，在調配物中使用適於滲透障壁之滲透劑。此類滲透劑一般為此項技術中已知，且對於經黏膜投與，包括例如膽汁鹽及梭鏈孢酸衍生物。此外，清潔劑可用於促進滲透。經黏膜投與例如可經由經鼻噴霧劑或栓劑（經直腸或***）進行。Administration can also be by transmucosal, topical, transdermal, or inhalation means. For transmucosal, topical or transdermal administration, penetrants suitable for penetrating barriers are used in the formulation. Such penetrants are generally known in the art, and for transmucosal administration include, for example, bile salts and fusidic acid derivatives. Additionally, cleaning agents can be used to facilitate penetration. Transmucosal administration, for example, can be via nasal sprays or suppositories (rectal or vaginal).

本發明之局部組合物藉由選擇此項技術中已知之適合的載劑而調配為油、乳霜、洗劑、軟膏及其類似物。適合的載劑包括植物或礦物油、白凡士林（白色軟性鏈烷烴）、分支鏈脂肪或油劑、動物脂肪及高分子量醇（大於C₁₂ ）。在另一實施例中，載劑為其中活性成分可溶之彼等物質。視需要，亦可包括乳化劑、穩定劑、保濕劑及抗氧化劑以及提供色彩或香味之試劑。用於局部施用之乳霜由礦物油、自乳化蜂蠟及水之混合物調配，在該混合物中混合有溶解於少量溶劑（例如油）中之活性成分。此外，藉由經皮手段進行之投與可包含經皮貼片或敷料，諸如浸漬有活性成分及視情況選用之一或多種此項技術中已知之載劑或稀釋劑之繃帶。為以經皮遞送系統形式投與，劑量投與在整個給藥方案中當然將為連續的而非間歇的。The topical compositions of the present invention are formulated as oils, creams, lotions, ointments and the like by selecting suitable carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than _C12 ). In another embodiment, the carriers are those in which the active ingredients are soluble. Emulsifiers, stabilizers, humectants, and antioxidants, as well as color or fragrance-providing agents, may also be included, if desired. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which the active ingredient is dissolved in a small amount of solvent, such as an oil. In addition, administration by transdermal means may comprise a transdermal patch or dressing, such as a bandage impregnated with the active ingredient and optionally with one or more carriers or diluents known in the art. To be administered in a transdermal delivery system, the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen.

所投與之各種化合物之量可藉由標準程序，考慮諸如化合物IC₅₀ 、化合物之生物半衰期、個體之年齡、身材及體重以及所治療之適應症之因素來測定。此等及其他因素之重要性為一般熟習此項技術者所熟知。一般而言，劑量將在約0.01與50 mg/kg，或0.1與20 mg/kg之所治療個體之間。可使用多劑量。The amount of each compound administered can be determined by standard procedures, taking into account factors such as the _IC50 of the compound, the biological half-life of the compound, the age, stature and weight of the individual, and the indication being treated. The importance of these and other factors is well known to those of ordinary skill in the art. Generally, the dosage will be between about 0.01 and 50 mg/kg, or 0.1 and 20 mg/kg of the subject being treated. Multiple doses may be used.

本發明之化合物亦可與其他用於治療相同疾病之療法組合使用。此類組合使用包括在不同時間投與化合物及一或多種其他治療劑，或共同投與化合物及一或多種其他療法。在一些實施例中，劑量可針對本發明化合物中之一或多者或組合使用之其他治療劑藉由一般熟習此項技術者熟知之方法進行改良，例如給與量相對於單獨使用之化合物或療法降低。The compounds of the present invention may also be used in combination with other therapies used to treat the same disease. Such combined use includes administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapies. In some embodiments, the dosage can be modified for one or more of the compounds of the invention or other therapeutic agents used in combination by methods well known to those of ordinary skill in the art, eg, the amount administered relative to the compound used alone or therapy decreased.

應理解，組合使用包括與其他療法、藥物、醫學程序等一起使用，其中另一療法或程序可在與本發明化合物不同的時間（例如在較短時間內，諸如在若干小時（例如1、2、3、4-24小時內），或在較長時間（例如1-2天、2-4天、4-7天、1-4週）內投與，或與本發明之化合物同時投與。組合使用亦包括與一次性或不頻繁地投與之療法或醫學程序（諸如手術），以及在另一療法或程序之前或之後的較短時間或較長時間內投與之本發明之化合物一起使用。在一些實施例中，本發明提供本發明之化合物及藉由不同投與途徑或藉由相同投與途徑遞送之一或多種其他藥物治療劑之遞送。用於任何投藥途徑之組合使用包括在任何調配物中共同遞送本發明之化合物及藉由相同投與途徑遞送之一或多種其他藥物治療劑，包括其中兩種化合物以使得在投與時保持其治療活性之方式化學連接之調配物。在一個態樣中，另一藥物療法可與本發明之一或多種化合物共同投與。藉由共同投與之組合使用包括投與化學接合化合物之共調配物或調配物，或在彼此之較短時間內（例如在1小時、2小時、3小時、至多24小時內）投與單獨調配物中之兩種或兩種以上化合物，該等化合物藉由相同或不同途徑投與。單獨調配物之共同投與包括藉由經由一種裝置（例如相同吸入裝置、相同注射器等）遞送來共同投與，或在彼此之較短時間內由單獨裝置投與。本發明之化合物及藉由相同途徑遞送之一或多種額外藥物療法之共同調配物包括共同製備材料，使得其可藉由一種裝置（包括在一種調配物中組合之單獨化合物，或經改質使得其為化學接合，但仍保持其生物活性之化合物）投與。此類化學接合化合物可具有活體內實質上維持之鍵聯，或該鍵聯可活體內分解而使兩種活性組分分離。IV. 使用方法 It is to be understood that use in combination includes use with other therapies, drugs, medical procedures, etc., where the other therapy or procedure may be administered at a different time (eg, within a shorter period of time, such as within several hours (eg, 1, 2) from the compound of the present invention , 3, 4-24 hours), or administered within a longer period of time (such as 1-2 days, 2-4 days, 4-7 days, 1-4 weeks), or administered simultaneously with the compounds of the present invention Use in combination also includes administration of a therapy or medical procedure (such as surgery) once or infrequently, and administration of a compound of the invention for a shorter or longer period of time before or after another therapy or procedure For use together. In some embodiments, the present invention provides the compounds of the present invention and the delivery of one or more other pharmaceutical therapeutic agents by different routes of administration or by the same route of administration. Combination use for any route of administration Included in any formulation are the co-delivery of a compound of the present invention and the delivery of one or more other pharmacotherapeutic agents by the same route of administration, including formulations in which the two compounds are chemically linked in such a way that their therapeutic activity is retained when administered In one aspect, another drug therapy can be co-administered with one or more compounds of the invention. Co-formulations or formulations including administration of chemically conjugated compounds are used in combination by co-administration, or in each other administration of two or more compounds in separate formulations, administered by the same or different routes, over a shorter period of time (eg, within 1 hour, 2 hours, 3 hours, up to 24 hours). Co-administration of formulations includes co-administration by delivery via one device (eg, the same inhaler device, same syringe, etc.), or administration by separate devices within a shorter period of time from each other. The compounds of the present invention are administered by the same Co-formulations that deliver one or more additional drug therapies include co-preparation of materials such that they can be delivered by a device (including separate compounds combined in a formulation, or modified so that they are chemically conjugated, but remain Its biologically active compounds) are administered. Such chemically conjugated compounds can have linkages that are substantially maintained in vivo, or the linkages can be decomposed in vivo to separate the two active components. IV. METHODS OF USE

方法及化合物將通常用於人類個體之療法中。然而，其亦可用於治療其他動物個體中之類似或相同適應症。The methods and compounds will generally be used in the therapy of human subjects. However, it may also be used to treat similar or identical indications in other animal subjects.

在某些實施例中，患者年齡為60歲或更大且在第一線癌症療法之後復發。在某些實施例中，患者年齡為18歲或更大且為在第二線癌症療法之後的復發性或難治性。在某些實施例中，患者年齡為60歲或更大且對第一線癌症療法為原發性難治性。在某些實施例中，患者年齡為70歲或更大且先前未經治療。在某些實施例中，患者年齡為70歲或更大且不夠資格接受癌症療法及/或不太可能受益於癌症療法。In certain embodiments, the patient is 60 years of age or older and has relapsed after first-line cancer therapy. In certain embodiments, the patient is 18 years of age or older and is relapsed or refractory following second line cancer therapy. In certain embodiments, the patient is 60 years of age or older and is primary refractory to first line cancer therapy. In certain embodiments, the patient is 70 years of age or older and has not been previously treated. In certain embodiments, the patient is 70 years of age or older and is ineligible for and/or unlikely to benefit from cancer therapy.

在某些實施例中，本文中所提供之方法中使用之治療有效量為至少10 mg/天。在某些實施例中，治療有效量為10、50、90、100、135、150、200、250、300、350、400、450、500、600、700、800、900、1000、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2500 mg/天。在其他實施例中，治療有效量為10、50、90、100、135、150、200、250、300、350、400、450、500、600、700、800、900、1000、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2500、3000、3500、4000、4500、5000 mg/天或更多。在某些實施例中，連續投與化合物。In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg/day. In certain embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300 , 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500 mg/day. In other embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg/day or more. In certain embodiments, the compound is administered continuously.

在某些實施例中，本文中提供一種用於治療由CD73介導之疾病或病況之方法，其藉由向患有疾病或病況之哺乳動物投與至少10、50、90、100、135、150、200、250、300、350、400、450、500、600、700、800、900、1000、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2500、3000、3500、4000、4500、5000 mg/天之如實施例1-36中之一者之化合物中所描述之化合物中之任一者，或其醫藥學上可接受之鹽、氘代類似物、互變異構體或立體異構體，且其中化合物係空腹投與。In certain embodiments, provided herein is a method for treating a disease or condition mediated by CD73 by administering to a mammal having the disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg/day of any one of the compounds described in the compound of one of Examples 1-36, or a pharmaceutically acceptable salt, deuterated analog, mutual isomers or stereoisomers, and wherein the compound is administered on an empty stomach.

本發明之實施例 38 係關於用於治療患有由CD73介導之疾病或病況之個體之方法，該方法包含向個體投與有效量之如實施例1-35（或適用時之其任何子實施例）中之一者之化合物或其醫藥學上可接受之鹽、氘代類似物、互變異構體或立體異構體，或如實施例36-37中之一者之醫藥組合物。 Embodiment 38 of the present invention pertains to a method for treating an individual suffering from a disease or condition mediated by CD73, the method comprising administering to the individual an effective amount of a drug as in Examples 1-35 (or any subgroup thereof, as applicable) A compound of one of Examples) or a pharmaceutically acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition of one of Examples 36-37.

本發明之實施例 39 係關於如實施例38之用於治療疾病或病況之方法，其中疾病或病況為贅生性病症、癌症、年齡相關之疾病、發炎性病症、認知病症及或神經退化性疾病。 Embodiment 39 of the present invention relates to the method for treating a disease or condition as in Embodiment 38, wherein the disease or condition is a neoplastic disorder, cancer, age-related disease, inflammatory disorder, cognitive disorder, and/or neurodegenerative disease .

本發明之實施例 40 係關於如實施例38之用於治療疾病或病況之方法，其中該疾病或病況係膀胱癌、大腸直腸癌、胃癌、膽囊癌、多形性神經膠質母細胞瘤、神經膠質瘤、白血病、淋巴瘤、肺癌、乳癌、黑色素瘤、多發性骨髓瘤、卵巢癌、***癌、胰腺癌、甲狀腺癌、肝纖維化、阿茲海默氏病、多發性硬化症或帕金森氏病。 Embodiment 40 of the present invention pertains to the method for treating a disease or condition as in Embodiment 38, wherein the disease or condition is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, glioblastoma multiforme, neuroblastoma Glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, liver fibrosis, Alzheimer's disease, multiple sclerosis, or Parkinson's disease.

本發明之實施例 40 （ a ） 係關於如實施例38之用於治療疾病或病況之方法，其中該疾病或病況係膀胱癌、大腸直腸癌、胃癌、膽囊癌、多形性神經膠質母細胞瘤、神經膠質瘤、白血病、淋巴瘤、肺癌、乳癌、黑色素瘤、多發性骨髓瘤、卵巢癌、***癌、胰腺癌、甲狀腺癌、肺纖維化、肝纖維化、阿茲海默氏病、多發性硬化症或帕金森氏病。 Embodiment 40 ( a ) of the present invention pertains to the method for treating a disease or condition as in Embodiment 38, wherein the disease or condition is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, polymorphic glioblastoma tumor, glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, pulmonary fibrosis, liver fibrosis, Alzheimer's disease, Multiple sclerosis or Parkinson's disease.

本發明之實施例 41 係關於如實施例40之用於治療疾病或病況之方法，其中淋巴瘤係成人T細胞淋巴瘤、AIDS相關淋巴瘤、未分化大細胞淋巴瘤、血管免疫母細胞T細胞淋巴瘤、B細胞淋巴瘤、伯基特氏淋巴瘤（Burkitt's lymphoma）、皮膚T細胞淋巴瘤、彌漫性大B細胞淋巴瘤、腸病相關T細胞淋巴瘤、濾泡性淋巴瘤、肝脾T細胞淋巴瘤、霍奇金氏淋巴瘤（Hodgkin's lymphoma）、非霍奇金氏淋巴瘤、MALT淋巴瘤、套細胞淋巴瘤、邊緣區B細胞淋巴瘤、原發滲出性淋巴瘤或T細胞淋巴瘤。 Embodiment 41 of the present invention pertains to the method for treating a disease or condition as in Embodiment 40, wherein the lymphoma is adult T cell lymphoma, AIDS-related lymphoma, undifferentiated large cell lymphoma, angioimmunoblastic T cells Lymphoma, B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, primary effusion lymphoma, or T-cell lymphoma .

本發明之實施例 42 係關於如實施例40之用於治療疾病或病況之方法，其中白血病係成人T細胞白血病、侵襲性NK細胞白血病、B細胞慢性淋巴球性白血病、急性單核球白血病、急性前髓細胞白血病、B細胞前淋巴球白血病、急性嗜酸性球白血病、急性紅血球白血病、急性淋巴母細胞白血病、急性巨核母細胞白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病或肥大細胞白血病。 Embodiment 42 of the present invention relates to the method for treating a disease or condition as in Embodiment 40, wherein the leukemia is adult T cell leukemia, aggressive NK cell leukemia, B cell chronic lymphocytic leukemia, acute monocytic leukemia, Acute premyeloid leukemia, B-cell prelymphoblastic leukemia, acute eosinophilic leukemia, acute erythrocyte leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia Leukemia or mast cell leukemia.

本發明之實施例 43 係關於如實施例38之用於治療疾病或病況之方法，其中該疾病或病況係腎癌、小細胞肺癌、非小細胞肺癌、急性骨髓性白血病、多發性骨髓瘤、彌漫性大B細胞淋巴瘤、乳癌或***癌。實施例 43 之子實施例 Embodiment 43 of the present invention relates to the method for treating a disease or condition as in Embodiment 38, wherein the disease or condition is renal cancer, small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, Diffuse large B-cell lymphoma, breast cancer, or prostate cancer. Sub-Example of Example 43

本發明之實施例 43 （ a ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係腎癌。 Embodiment 43 ( a ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is renal cancer.

本發明之實施例 43 （ b ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係小細胞肺癌。 Embodiment 43 ( b ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is small cell lung cancer.

本發明之實施例 43 （ c ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係非小細胞肺癌。 Embodiment 43 ( c ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is non-small cell lung cancer.

本發明之實施例 43 （ d ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係急性骨髓性白血病。 Embodiment 43 ( d ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is acute myeloid leukemia.

本發明之實施例 43 （ e ） 係關於用於治療如實施例43之疾病或病況之方法，其中該疾病或病況係多發性骨髓瘤。 Embodiment 43 ( e ) of the present invention pertains to a method for treating a disease or condition such as embodiment 43, wherein the disease or condition is multiple myeloma.

本發明之實施例 43 （ f ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係彌漫性大B細胞淋巴瘤。 Embodiment 43 ( f ) of the present invention pertains to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is diffuse large B-cell lymphoma.

本發明之實施例 43 （ g ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係乳癌。 Embodiment 43 ( g ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is breast cancer.

本發明之實施例 43 （ h ） 係關於如實施例43之用於治療疾病或病況之方法，其中該疾病或病況係***癌。V. 組合療法 Embodiment 43 ( h ) of the present invention relates to the method for treating a disease or condition as in Embodiment 43, wherein the disease or condition is prostate cancer. V. Combination Therapy

CD73調節劑可與另一種藥理學活性化合物或兩種或兩種以上其他藥理學活性化合物有效組合，尤其在治療癌症方面。在一個實施例中，組合物包括如本文中所描述之任何一或多種化合物以及一或多種在治療學上對相同疾病適應症有效之化合物，其中該等化合物對疾病適應症具有協同作用。在一個實施例中，該組合物包括有效治療癌症之如本文所描述之任何一或多種化合物以及有效治療相同癌症之一或多種其他化合物，此外其中該等化合物協同有效於治療癌症。與其他腺苷軸阻斷劑（諸如針對 CD39 、 CD38 、 A2AR 或 A2BR 之藥劑）組合： A CD73 modulator can be effectively combined with another pharmacologically active compound or two or more other pharmacologically active compounds, especially in the treatment of cancer. In one embodiment, the composition includes any one or more compounds as described herein and one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition comprises any one or more compounds as described herein effective to treat cancer and one or more other compounds effective to treat the same cancer, further wherein the compounds are synergistically effective to treat cancer. In combination with other adenosine axis blockers such as agents targeting CD39 , CD38 , A2AR or A2BR :

在生理條件下，生物流體及細胞外空間中之ATP及NAD⁺ 較低（30-100 nM），而其細胞內濃度係在mM範圍內。在細胞活化、應力、低氧及組織破壞後，其自細胞釋放。過量之細胞外ATP由外核苷酸酶，諸如CD39或外核苷酸焦磷酸酶/磷酸二酯酶（例如ENPP1）迅速水解，產生ADP且最終產生AMP。或者，AMP可以藉由胞外-NAD-葡糖水解酶CD38及ENPP1之協同作用而自細胞外菸鹼醯胺腺嘌呤二核苷酸（NAD+）產生。AMP主要藉由CD73進一步水解為腺苷，而藉由鹼性磷酸酶則效率較低。腺苷經由G-蛋白偶聯受體A1、A2a、A2b及A3活化信號傳導路徑。在參與響應於免疫細胞活化上調之A2a或A2b受體後，腺苷觸發細胞內cAMP之增加且導致免疫功能之顯著抑制。支持靶向腺苷能路徑之多個點之臨床前研究可為癌症治療提供顯著治療益處。Perrot, I.等人，《阻斷靶向CD39/CD73免疫抑制路徑之抗體在聯合癌症療法中釋放免疫反應（Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies）》。《細胞報導 （Cell Rep. ）》27 , 2411-2425.e9（2019）, Young, A.等人，《共抑制CD73及A2AR腺苷信號傳導改良抗腫瘤免疫反應（Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses）》。《癌細胞 （Cancer Cell ）》30 , 391-403（2016）。組合免疫檢查點阻斷： Under physiological conditions, ATP and NAD ⁺ are low (30-100 nM) in biological fluids and in the extracellular space, while their intracellular concentrations are in the mM range. It is released from cells following cellular activation, stress, hypoxia, and tissue destruction. Excess extracellular ATP is rapidly hydrolyzed by exonucleotidase enzymes such as CD39 or exonucleotide pyrophosphatase/phosphodiesterase (eg ENPP1) to produce ADP and ultimately AMP. Alternatively, AMP can be produced from extracellular nicotinamide adenine dinucleotide (NAD+) by the synergy of the extracellular-NAD-glucohydrolase CD38 and ENPP1. AMP is further hydrolyzed to adenosine mainly by CD73 and less efficiently by alkaline phosphatase. Adenosine activates signaling pathways via G-protein coupled receptors Al, A2a, A2b, and A3. Following engagement with A2a or A2b receptors that are upregulated in response to immune cell activation, adenosine triggers an increase in intracellular cAMP and results in a marked suppression of immune function. Preclinical studies that support targeting multiple points of the adenosinergic pathway could provide significant therapeutic benefits for cancer therapy. Perrot, I. et al., Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies. " Cell Rep. " 27 , 2411-2425.e9 (2019), Young, A. et al., "Co-inhibition of CD73 and A2AR adenosine signaling improves antitumor immune response (Co-inhibition of CD73 and A2AR)" Adenosine Signaling Improves Anti-tumor Immune Responses). Cancer Cell 30 , 391-403 (2016). Combination immune checkpoint blockade:

抗PD-1及抗CTLA4檢查點阻斷均可以與抗CD73或抗A2a療法協同作用。Allard, B.等人，《靶向CD73增強抗PD-1及抗CTLA-4 mAb之抗腫瘤活性（Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs）》。《臨床癌症研究 （Clin. Cancer Res. ）》19, 5626-5636（2013）；Hay, C. M.等人，《用MEDI9447在腫瘤微環境中靶向CD73（Targeting CD73 in the tumor microenvironment with MEDI9447）》。《腫瘤免疫學（Oncoimmunology）》5, 1-10（2016）；Willingham, S. B.等人，《在臨床前模型中，與CPI-444之A2AR拮抗作用誘導抗腫瘤反應且加強對抗PD-（L）1及抗CTLA-4之效力（A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Ef fi cacy to Anti - PD- (L) 1 and Anti - CTLA-4 in Preclinical Models）》。6, 22-25（2018）；Waickman, A. T.& Powell, J. D.《美國國立衛生研究院（NIH Public Access.）》61, 917-926（2013）；Beavis, P. A.等人，《腺苷受體2A阻斷經由增強抗腫瘤T細胞反應提高抗PD-1之效力（Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses）》。3,（2015）；Mittal, D.等人，《阻斷PD-1及腺苷A2A受體之抗轉移作用（Antimetastatic Effects of Blocking PD-1 and the Adenosine A2A Receptor）》。3, 3652-3659（2014）。展示協同作用在CD8+ T細胞及IFN-γ依賴性方式中促進一些腫瘤模型中之生長延遲及甚至完全排斥。Allard, B.等人，《靶向CD73增強抗PD-1及抗CTLA-4 mAb之抗腫瘤活性（Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs）》。《臨床癌症研究 》19, 5626-5636（2013）；Hay, C. M.等人，《用MEDI9447在腫瘤微環境中靶向CD73》。《腫瘤免疫學》5, 1-10（2016）；Willingham, S. B.等人，《在臨床前模型中，與CPI-444之A2AR拮抗作用誘導抗腫瘤反應且加強對抗PD-（L）1及抗CTLA-4之效力》。6, 22-25（2018）；Beavis, P. A.等人，腺苷受體2A阻斷經由增強抗腫瘤T細胞反應提高抗PD-1之效力。3,（2015）。潛在CD73抑制劑可以與靶向T細胞相關抑制性分子之其他試劑，諸如PDL1、LAG-3、TIGIT、TIM-3、VISTA、B7-H3等協同作用。與 TNFA 超家族成員之促效劑組合： Both anti-PD-1 and anti-CTLA4 checkpoint blockade can be synergistic with anti-CD73 or anti-A2a therapy. Allard, B. et al., "Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs". "Clin. Cancer Res. " 19, 5626-5636 (2013); Hay, CM et al., "Targeting CD73 in the tumor microenvironment with MEDI9447". Oncoimmunology 5, 1-10 (2016); Willingham, SB et al., A2AR antagonism with CPI-444 induces antitumor responses and potentiates anti-PD-(L) in preclinical models 1 and the efficacy of anti-CTLA-4 (A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Ef fi cacy to Anti - PD- (L) 1 and Anti - CTLA-4 in Preclinical Models). 6, 22-25 (2018); Waickman, AT & Powell, JD, NIH Public Access. 61, 917-926 (2013); Beavis, PA et al., Adenosine Receptor 2A Blockade Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses”. 3, (2015); Mittal, D. et al., "Antimetastatic Effects of Blocking PD-1 and the Adenosine A2A Receptor". 3, 3652-3659 (2014). It was shown that synergy promotes growth retardation and even complete rejection in some tumor models in a CD8+ T cell and IFN-γ-dependent manner. Allard, B. et al., "Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs". Clinical Cancer Research 19, 5626-5636 (2013); Hay, CM et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Tumor Immunology 5, 1-10 (2016); Willingham, SB et al., A2AR antagonism with CPI-444 induces antitumor responses and potentiates anti-PD-(L)1 and anti-PD-(L)1 in preclinical models Effectiveness of CTLA-4." 6, 22-25 (2018); Beavis, PA, et al. Adenosine receptor 2A blockade increases anti-PD-1 efficacy by enhancing anti-tumor T cell responses. 3, (2015). Potential CD73 inhibitors may synergize with other agents targeting T cell-associated inhibitory molecules, such as PDL1, LAG-3, TIGIT, TIM-3, VISTA, B7-H3, and the like. In combination with agonists of members of the TNFA superfamily:

在抗原引發的T細胞之表面上針對腫瘤壞死因子受體（TNFR）超家族成員（諸如4-1BB、GITR及OX40）之促效劑抗體處於臨床前及臨床試驗的各個階段。然而，其作為單一藥劑呈現有限治療益處。在腫瘤微環境中藉由TGF-β持續的T細胞上之CD73表現阻礙此等促效劑抗體之治療活性。CD73抑制劑可克服對TNFR促效劑之抗性且增強其效力。與靶向療法之組合： Agonist antibodies against tumor necrosis factor receptor (TNFR) superfamily members such as 4-1BB, GITR and OX40 on the surface of antigen-primed T cells are in various stages of preclinical and clinical trials. However, it presents limited therapeutic benefit as a single agent. The persistence of CD73 expression on T cells by TGF-beta in the tumor microenvironment hinders the therapeutic activity of these agonist antibodies. CD73 inhibitors can overcome resistance to TNFR agonists and enhance their efficacy. In combination with targeted therapy:

乳癌中CD73之高表現與針對曲妥珠單抗（Trastuzumab）（抗HER2/ErbB2 mAb）之抗性相關。Turcotte, M.等人，《CD73促進對HER2/ErbB2抗體療法之抗性（CD73 promotes resistance to HER2/ErbB2 antibody therapy）》。《癌症研究 （Cancer Res. ）》77 , 5652-5663（2017）。阻斷CD73展示增強抗ErbB2 mAb治療***腫瘤以及肺癌轉移之活性。同上 。High CD73 expression in breast cancer correlates with resistance to Trastuzumab (anti-HER2/ErbB2 mAb). Turcotte, M. et al. CD73 promotes resistance to HER2/ErbB2 antibody therapy. Cancer Res. 77 , 5652-5663 (2017). Blockade of CD73 was shown to enhance the activity of anti-ErbB2 mAbs in the treatment of breast tumors as well as lung cancer metastasis. Ditto .

在含有BRAF-突變型腫瘤之黑色素瘤患者中觀測到CD73表現升高。A2AR拮抗劑經展示在攜帶BRAF-突變型腫瘤之小鼠中增強BRAF及MEK抑制之效力。Young, A.等人，在BRAF-突變型黑色素瘤中靶向腺苷減少腫瘤生長及轉移（Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis）。《癌症研究》77, 4684-4696（2017）。類似地，CD73抑制劑可以改善BRAF及MEK抑制劑之治療益處。Elevated CD73 expression was observed in melanoma patients with BRAF-mutant tumors. A2AR antagonists were shown to potentiate BRAF and MEK inhibition in mice bearing BRAF-mutant tumors. Young, A. et al. Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis. Cancer Research 77, 4684-4696 (2017). Similarly, CD73 inhibitors may improve the therapeutic benefit of BRAF and MEK inhibitors.

CD73在含有EGFR突變之NSCLC中過度表現。Inoue, Y.等人，CD73及A2A腺苷受體表現對非小細胞肺癌之預後影響（Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer）。《腫瘤標靶（Oncotarget）》8, 8738-8751（2017）。類似地，CD73抑制劑可以改善BRAF及MEK抑制劑之治療益處。CD73在含有EGFR突變之非小細胞肺癌（NSCLC）中過度表現（Inoue, Y.等人，《CD73及A2A腺苷受體表現對非小細胞肺癌之預後影響（Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer）》。《腫瘤標靶》8, 8738-8751（2017））且其表現與EGFR表現在NSCLC、肝臟、乳癌及神經膠質母細胞瘤中係正相關。Zhu, J.等人，《CD73/NT5E係miR-30a-5p之標靶，且在非小細胞肺癌之發病機理中起重要作用（CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer）》。《分子癌症 （Mol. Cancer ）》16, 1-15（2017）；Shali, S.等人，《胞外-5'-核苷酸酶（CD73）係肝細胞癌之潛在標靶（Ecto-5'-nucleotidase (CD73) is a potential target of hepatocellular carcinoma）》。《細胞生理學雜誌 （J. Cell. Physiol. ）》234, 10248-10259（2019）；Zhi, X.等人，《潛在預後生物標誌物CD73調節人類乳癌中之表皮生長因子受體表現（Potential Prognostic Biomarker CD73 Regulates Epidermal Growth Factor Receptor Expression in Human Breast Cancer）》。《IUBMB Life.》64, 911-920（2012）；Ludwig, H.等人，《CD73（胞外-5'-核苷酸酶）在165個神經膠質母細胞瘤中藉由免疫組織化學及電鏡組織化學之表現（Expression of CD 73 ( ecto-5 ' -nucleotidase ) in 165 glioblastomas by immunohistochemistry and electronmicroscopic histochemistry）》, 《抗癌研究 （Anticancer Res. ）》19, 1747-52（1999）。發現CD73促進若干類型之癌細胞（包括NSCLC、肝臟及乳癌細胞）中之EGFR表現。Zhu, J.等人，《CD73/NT5E係miR-30a-5p之標靶，且在非小細胞肺癌之發病機理中起重要作用》。《分子癌症 》16, 1-15（2017）；Shali, S.等人，《胞外-5'-核苷酸酶（CD73）係肝細胞癌之潛在標靶》。《細胞生理學雜誌 》234, 10248-10259（2019）；Zhi, X.等人，潛在預後生物標誌物CD73調節人類乳癌中之表皮生長因子受體表現。《IUBMB Life. 》64, 911-920（2012）。先前研究已展示CD73之抑制降低NSCLC及肝癌細胞之增殖（Zhu, J.等人，CD73/NT5E係miR-30a-5p之標靶，且在非小細胞肺癌之發病機理中起重要作用。《分子癌症 》16, 1-15（2017）；Shali, S.等人，《胞外-5'-核苷酸酶（CD73）係肝細胞癌之潛在標靶》。《細胞生理學雜誌 》234, 10248-10259（2019））及乳癌細胞之遷移及侵襲。Zhi, X.等人，潛在預後生物標誌物CD73調節人類乳癌中之表皮生長因子受體表現。《IUBMB Life 》64, 911-920（2012）。CD73抑制可潛在地改善EGFR抑制劑在此等癌症中之治療結果。CD73抑制劑與EGFR抑制劑之組合可產生比單一藥劑更好的治療益處。與照射及化學療法組合： CD73 is overexpressed in NSCLC harboring EGFR mutations. Inoue, Y. et al., Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8, 8738-8751 (2017). Similarly, CD73 inhibitors may improve the therapeutic benefit of BRAF and MEK inhibitors. CD73 is overexpressed in EGFR-mutated non-small cell lung cancer (NSCLC) (Inoue, Y. et al., "Prognostic impact of CD73 and A2A adenosine receptor expression on non-small cell lung cancer") expression in non-small-cell lung cancer)”. “Tumor Targets” 8, 8738-8751 (2017)) and its expression is positively correlated with EGFR expression in NSCLC, liver, breast cancer and glioblastoma. Zhu, J. et al., "CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer (CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer). " Mol . Cancer " 16, 1-15 (2017); Shali, S. et al., "Extracellular-5'-nucleotidase (CD73) is a potential target for hepatocellular carcinoma (Ecto- 5'-nucleotidase (CD73) is a potential target of hepatocellular carcinoma). J. Cell. Physiol. 234 , 10248-10259 (2019); Zhi, X. et al., Potential prognostic biomarker CD73 modulates epidermal growth factor receptor expression in human breast cancer (Potential Prognostic Biomarker CD73 Regulates Epidermal Growth Factor Receptor Expression in Human Breast Cancer). "IUBMB Life." 64, 911-920 (2012); Ludwig, H. et al., "CD73 (extracellular-5'-nucleotidase) in 165 glioblastomas by immunohistochemistry and Electron Microscopic Histochemistry (Expression of CD 73 (ecto-5 '-nucleotidase) in 165 glioblastomas by immunohistochemistry and electronmicroscopic histochemistry)", " Anticancer Research ( Anticancer Res. )" 19, 1747-52 (1999). CD73 was found to promote EGFR expression in several types of cancer cells, including NSCLC, liver and breast cancer cells. Zhu, J. et al. "CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer." Molecular Cancer 16, 1-15 (2017); Shali, S. et al., "Extracellular-5'-nucleotidase (CD73) is a potential target for hepatocellular carcinoma." Journal of Cell Physiology 234, 10248-10259 (2019); Zhi, X. et al. Potential prognostic biomarker CD73 modulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life. 64, 911-920 (2012). Previous studies have shown that inhibition of CD73 reduces proliferation of NSCLC and liver cancer cells (Zhu, J. et al., CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer." Molecular Cancer 16, 1-15 (2017); Shali, S. et al. Extracellular-5'-nucleotidase (CD73) is a potential target for hepatocellular carcinoma. Journal of Cell Physiology 234 , 10248-10259 (2019)) and migration and invasion of breast cancer cells. Zhi, X. et al. Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life 64, 911-920 (2012). CD73 inhibition could potentially improve the therapeutic outcome of EGFR inhibitors in these cancers. Combinations of CD73 inhibitors and EGFR inhibitors may yield better therapeutic benefit than single agents. In combination with irradiation and chemotherapy:

放射線療法及化學療法可以誘導ATP自癌細胞釋放。其亦增強CD73及其他成員在腺苷軸中之表現。CD73/腺苷系統在腫瘤微環境中之活性不僅與增加之腫瘤生長及腫瘤免疫逃逸有關，且亦與放射誘導之不良晚期作用（諸如肺纖維化）有關。Wirsdorfer, F.等人，藉由胞外-50-核苷酸酶（CD73）之細胞外腺苷產生增強放射誘導之肺纖維化（Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation-induced lung fibrosis）。《癌症研究 》76, 3045-3056（2016）。阻斷CD73活性可以增強放射療法之抗腫瘤效力（Wennerberg, E.等人，《腺苷調節放射療法誘導之抗腫瘤免疫（Adenosine regulates radiation therapy-induced anti-tumor immunity）》。《癌症免疫療法雜誌 （J. Immunother. Cancer ）》3, P378（2015）；Wennerberg, E.等人，《腺苷產生藉由消除CD103+DC之補充及活化來限制放射誘導之腫瘤免疫原性（Adenosine generation limits radiation-induced tumor immunogenicity by abrogating recruitment and activation of CD103 + DCs）》。《免疫學雜誌 （J. Immunol. ）》198, 154.6（2017））及化學治療劑，諸如多柔比星（Doxorubincin）、紫杉醇（Loi, S.等人，《CD73在三環陰性乳癌中促進蒽環黴素抗性及不良預後（CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer.）》doi:10.1073/pnas.1222251110.），且米托蒽醌（Mitoxantrone）及亦降低放療療法誘導之對正常組織之後期毒性（Wirsdorfer，F.等人，《藉由胞外-50-核苷酸酶（CD73）之細胞外腺苷產生增強放射誘導之肺纖維化（Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation-induced lung fibrosis）》。《癌症研究 》76, 3045-3056（2016）；de Leve, S.等人，《CD73/Ado系統-RT誘導之不良晚期效應中之新參與者（The CD73/Ado System-A New Player in RT Induced Adverse Late Effects）》。《癌症 》（巴塞爾）11, 1578（2019）），從而改進放射療法及化學療法之治療增益。與過繼性 T 細胞轉移或 DC 疫苗組合： Radiation therapy and chemotherapy can induce the release of ATP from cancer cells. It also enhances the expression of CD73 and other members in the adenosine axis. The activity of the CD73/adenosine system in the tumor microenvironment is not only associated with increased tumor growth and tumor immune escape, but also with radiation-induced adverse late effects such as pulmonary fibrosis. Wirsdorfer, F. et al., Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation- induced lung fibrosis). Cancer Research 76, 3045-3056 (2016). Blockade of CD73 activity enhances the antitumor efficacy of radiation therapy (Wennerberg, E. et al., "Adenosine regulates radiation therapy-induced anti-tumor immunity." Journal of Cancer Immunotherapy ( J. Immunother. Cancer )” 3, P378 (2015); Wennerberg, E. et al., Adenosine generation limits radiation-induced tumor immunogenicity by eliminating CD103+ DC replenishment and activation -induced tumor immunogenicity by abrogating recruitment and activation of CD103+ DCs). J. Immunol. 198 , 154.6 (2017)) and chemotherapeutic agents such as doxorubincin, paclitaxel ( Loi, S. et al., CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. doi:10.1073/pnas.1222251110.) , and Mitoxantrone and also reduced radiotherapy-induced late toxicity to normal tissues (Wirsdorfer, F. et al., "Extracellular adenosine by extracellular-50-nucleotidase (CD73)" Extracellular adenosine production by ecto-50-nucleotidase (CD73) enhances radiation-induced lung fibrosis.” Cancer Research 76, 3045-3056 (2016); de Leve, S. et al. , "The CD73/Ado System-A New Player in RT Induced Adverse Late Effects." Cancer (Basel) 11, 1578 (2019) ), thereby improving the therapeutic gain of radiotherapy and chemotherapy. In combination with adoptive T cell transfer or DC vaccine:

過繼性T細胞轉移（腫瘤浸潤性淋巴細胞療法及CAR-T療法）產生針對某些類型之惡性腫瘤之前所未有的臨床反應。已證明小鼠中之CD73阻斷與過繼性T細胞轉移之間存在協同作用。Wang, L.等人，《CD73在非造血及造血細胞中具有不同作用以促進小鼠中之腫瘤生長（CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice）》。《臨床研究雜誌 （J. Clin. Invest. ）》121, 2371-2382（2011）；Jin, D.等人，《腫瘤細胞上之CD73損害抗腫瘤T細胞反應：腫瘤誘導之免疫抑制之新機制（CD73 on tumor cells impairs anti-tumor T cell responses: a novel mechanism of tumor-induced immune suppression）》。《癌症研究 》70, 2245-2255（2011）。此藉由增強CD73阻斷在腫瘤部位過繼性轉移之腫瘤特異性T細胞之回歸來解釋。Wang, L.等人，《CD73在非造血及造血細胞中具有不同作用以促進小鼠中之腫瘤生長》。《臨床研究雜誌 》121, 2371-2382（2011）。Adoptive T cell transfer (tumor-infiltrating lymphocyte therapy and CAR-T therapy) produces unprecedented clinical responses against certain types of malignancies. Synergy between CD73 blockade and adoptive T cell transfer in mice has been demonstrated. Wang, L. et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest. 121, 2371-2382 (2011); Jin, D. et al., CD73 on tumor cells impairs antitumor T cell responses: a novel mechanism of tumor-induced immunosuppression (CD73 on tumor cells impairs anti-tumor T cell responses: a novel mechanism of tumor-induced immune suppression). Cancer Research 70, 2245-2255 (2011). This is explained by enhanced CD73 blocking the regression of adoptively transferred tumor-specific T cells at the tumor site. Wang, L. et al. "CD73 has distinct roles in non-hematopoietic and hematopoietic cells to promote tumor growth in mice." Journal of Clinical Investigation 121, 2371-2382 (2011).

旨在誘導具有免疫記憶體之腫瘤特異性效應T細胞之樹突狀細胞（DC）疫苗接種為一種癌症免疫療法之有前景的方法。需要其與靶向免疫抑制機制之其他療法之組合來改善結果。已展示靶向CD73可經由誘導腫瘤特異性T細胞活性來改進DC疫苗之效力。Arab, S.等人，《用腺苷受體拮抗劑及CD73抑制劑增強基於樹突狀細胞之治療性癌症疫苗之效力（Increased efficacy of a dendritic cell - based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor）》。《腫瘤生物學 （Tumor Biol. ）》1-8（2017）doi:10.1177/1010428317695021。Dendritic cell (DC) vaccination aimed at inducing tumor-specific effector T cells with immune memory is a promising approach for cancer immunotherapy. Combination with other therapies targeting immunosuppressive mechanisms is required to improve outcomes. Targeting CD73 has been shown to improve the efficacy of DC vaccines by inducing tumor-specific T cell activity. Arab, S. et al., "Increased efficacy of a dendritic cell - based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor"inhibitor)". Tumor Biol. 1-8 (2017) doi: 10.1177/1010428317695021.

在另一實施例中，本發明提供用於治療由CD73介導之疾病或病況之方法，其藉由向個體投與有效量之組合物，該組合物包括如本文中所描述之任何一或多種化合物與一或多種用於治療疾病之其他適合的療法之組合。肝纖維化 In another embodiment, the present invention provides a method for treating a disease or condition mediated by CD73 by administering to an individual an effective amount of a composition comprising any one as described herein or Combinations of various compounds with one or more other suitable therapies for the treatment of disease. Liver Fibrosis

肝纖維化發展為對慢性發炎及由酒精或病毒感染所致之持續肝臟損傷的反應。此病理過程係藉由肌纖維母細胞之活化及蓄積驅動。由於肌纖維母細胞分化，所以在肝星狀細胞、門脈成纖維細胞及纖維隔膜中上調CD73。Fausther, M.等人，《經活化之肝星狀細胞經由特異性SP1及SMAD啟動子元件上調胞外-5'-核苷酸酶/CD73之轉錄（Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements）》。《美國生理學雜誌 - 胃腸與肝臟生理學 （Am. J. Physiol. -Gastrointest.Liver Physiol. ）》303 ,（2012）。保護CD73缺陷小鼠免於肝纖維化之發展，表明其在纖維發生中之作用及腺苷產生。Peng, Z.等人，胞外-5'-核苷酸酶（CD73）介導之細胞外腺苷產生在肝纖維化中發揮重要作用（Ecto-5'-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis）。《FASEB J. 》22 , 2263-2272（2008）。CD73可適用於預防肝纖維化。多發性硬化症（ MS ） Liver fibrosis develops in response to chronic inflammation and persistent liver damage caused by alcohol or viral infection. This pathological process is driven by the activation and accumulation of myofibroblasts. CD73 is upregulated in hepatic stellate cells, portal fibroblasts and fibrous septa due to myofibroblast differentiation. Fausther, M. et al., Activated hepatic stellate cells upregulate transcription of ecto-5 via specific SP1 and SMAD promoter elements '-nucleotidase/CD73 via specific SP1 and SMAD promoter elements)". " American Journal of Physiology - Gastrointestinal and Liver Physiology ( Am. J. Physiol. - Gastrointest. Liver Physiol. )" 303 , (2012). Protects CD73-deficient mice from the development of liver fibrosis, suggesting its role in fibrogenesis and adenosine production. Peng, Z. et al. Ecto-5'-nucleotidase (CD73)-mediated extracellular adenosine production plays an important role in liver fibrosis production plays a critical role in hepatic fibrosis). FASEB J. 22 , 2263-2272 (2008). CD73 may be suitable for preventing liver fibrosis. Multiple Sclerosis ( MS )

MS係影響CNS之自體免疫疾病。在MS動物模型中，實驗性自體免疫腦脊髓炎（EAE）、髓鞘抗原特異性CD4+ T細胞展示在誘導CNS發炎、髓鞘脫失及神經退化中起一定作用。不管CD73在免疫抑制中之主要作用眾所周知，CD73-/-小鼠對EAE誘導具有高度抗性。Mills, J. H.等人，《在實驗性自體免疫腦脊髓炎期間，CD73為淋巴細胞進入中樞神經系統所需的（CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis）》。《美國科學院院刊 （Proc. Natl. Acad. Sci. U. S. A. ）》105 , 9325-9330（2008）。此藉由CD73及腺苷在EAE誘導期間在CNS淋巴細胞浸潤中之作用比其在調節神經發炎方面之作用更顯著來解釋。同上。 CD73抑制可適用於治療MS及其他神經發炎性疾病。MS is an autoimmune disease affecting the CNS. In animal models of MS, experimental autoimmune encephalomyelitis (EAE), display of myelin antigen-specific CD4+ T cells plays a role in inducing CNS inflammation, demyelination, and neurodegeneration. Despite the well-known primary role of CD73 in immunosuppression, CD73-/- mice are highly resistant to EAE induction. Mills, JH, et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 105 , 9325-9330 (2008). This is explained by a more pronounced role for CD73 and adenosine in CNS lymphocyte infiltration during EAE induction than in regulating neuroinflammation. Ditto. CD73 inhibition may be useful in the treatment of MS and other neuroinflammatory diseases.

本發明之實施例 44 係關於如實施例38-43中任一項或其任何子實施例之方法，其進一步包含投與一或多種額外治療劑。 Embodiment 44 of the present invention pertains to the method of any one of embodiments 38-43, or any sub-embodiments thereof, further comprising administering one or more additional therapeutic agents.

本發明之實施例 45 係關於如實施例44之方法，其中一或多種為以下中之一或多者：i）烷基化劑，其選自阿多來新（adozelesin）、六甲蜜胺（altretamine）、比折來新（bizelesin）、白消安（busulfan）、卡鉑（carboplatin）、卡波醌（carboquone）、卡莫司汀（carmustine）、苯丁酸氮芥（chlorambucil）、順鉑（cisplatin）、環磷醯胺（cyclophosphamide）、達卡巴

（dacarbazine）、雌氮芥（estramustine）、福莫司汀（fotemustine）、海普法姆（hepsulfam）、異環磷醯胺（ifosfamide）、英丙舒凡（improsulfan）、伊洛福芬（irofulven）、洛莫司汀（lomustine）、甲基二(氯乙基)胺（mechlorethamine）、美法侖（melphalan）、奧沙利鉑（oxaliplatin）、哌泊舒凡（piposulfan）、司莫司汀（semustine）、鏈脲菌（streptozocin）、替莫唑胺（temozolomide）、噻替派（thiotepa）及曲奧舒凡（treosulfan）；ii）抗生素，其選自博萊黴（bleomycin）、放線菌素（dactinomycin）、道諾黴素（daunorubicin）、小紅莓（doxorubicin）、表柔比星（epirubicin）、伊達比星（idarubicin）、美諾立爾（menogaril）、絲裂黴素（mitomycin）、米托蒽醌（mitoxantrone）、新卡他汀（neocarzinostatin）、噴司他汀（pentostatin）及普卡黴素（plicamycin）；iii）抗代謝物，其選自由以下組成之群：阿紮胞苷（azacitidine）、卡培他濱（capecitabine）、克拉屈濱（cladribine）、氯法拉濱（clofarabine）、阿糖胞苷（cytarabine）、地西他濱（decitabine）、氟尿苷（floxuridine）、氟達拉濱（fludarabine）、5-氟尿嘧啶（5-fluorouracil）、替加氟（ftorafur）、吉西他濱（gemcitabine）、羥基脲（hydroxyurea）、巰基嘌呤（mercaptopurine）、甲胺喋呤（methotrexate）、奈拉濱（nelarabine）、培美曲塞（pemetrexed）、雷替曲塞（raltitrexed）、硫鳥嘌呤（thioguanine）及曲美沙特（trimetrexate）；iv）免疫治療劑，其選自PD-1或PD-L1抑制劑；v）激素或激素拮抗劑，其選自由以下組成之群：恩雜魯胺（enzalutamide）、阿比特龍（abiraterone）、阿那曲唑（anastrozole）、雄激素（androgens）、布舍瑞林（buserelin）、己烯雌酚（diethylstilbestrol）、依西美坦（exemestane）、氟他胺（flutamide）、氟維司群（fulvestrant）、戈舍瑞林（goserelin）、艾多昔芬（idoxifene）、來曲唑（letrozole）、亮丙立德（leuprolide）、甲地孕酮（magestrol）、雷諾昔酚（raloxifene）、他莫昔芬（tamoxifen）及托瑞米芬（toremifene）；vi）紫杉烷（taxane），其選自DJ-927、多西他賽（docetaxel）、TPI 287、太平洋紫杉醇（paclitaxel）及DHA-太平洋紫杉醇（DHA-paclitaxel）；vii）類視黃素（retinoid），其選自亞利崔托寧（alitretinoin）、貝瑟羅汀（bexarotene）、非瑞替尼（fenretinide）、異維甲酸（isotretinoin）及維甲酸（tretinoin）；viii）生物鹼，其選自依託泊苷（etoposide）、高三尖杉酯鹼（homoharringtonine）、替尼泊苷（teniposide）、長春鹼（vinblastine）、長春新鹼（vincristine）、長春地辛（vindesine）及長春瑞賓（vinorelbine）；ix）抗血管生成劑，其選自AE-941（GW786034，Neovastat）、ABT-510、2-甲氧***（2-methoxyestradiol）、來那度胺（lenalidomide）及沙力度胺（thalidomide）；x）拓樸異構酶抑制劑，其選自安吖啶（amsacrine）、艾特咔林（edotecarin）、依昔替康（exatecan）、伊立替康（irinotecan）、SN-38(7-乙基-10-羥基-喜樹鹼)（SN-38 (7-ethyl-10-hydroxy-camptothecin)）、盧比替康（rubitecan）、拓朴替康（topotecan）及9-胺基喜樹鹼（9-aminocamptothecin）；xi）激酶抑制劑，其選自埃羅替尼（erlotinib）、吉非替尼（gefitinib）、夫拉平度（flavopiridol）、甲磺酸伊馬替尼（imatinib mesylate）、拉帕替尼（lapatinib）、索拉非尼（sorafenib）、蘋果酸舒尼替尼（sunitinib malate）、AEE-788、AG-013736、AMG 706、AMN107、BMS-354825、BMS-599626、UCN-01（7-羥基星孢菌素）（7-hydroxystaurosporine）、維羅非尼（vemurafenib）、達拉非尼（dabrafenib）、曲美替尼（trametinib）、考比替尼（cobimetinib）、司美替尼（selumetinib）及凡塔藍尼（vatalanib）；xii）靶向信號轉導抑制劑，其選自硼替佐米（bortezomib）、格爾德黴素（geldanamycin）及雷帕黴素（rapamycin）；xiii）生物反應調節劑，其選自咪喹莫特（imiquimod）、干擾素-α及介白素-2；xiv）IDO抑制劑；及xv）化學治療劑，其選自3-AP(3-胺基-2-羥基醛硫半腙)（3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone)）、阿曲生坦（altrasentan）、胺魯米特（aminoglutethimide）、阿那格雷（anagrelide）、天冬醯胺酶（asparaginase）、苔蘚蟲素-1（bryostatin-1）、西侖吉肽（cilengitide）、艾利莫耳（elesclomol）、甲磺酸艾日布林（eribulin mesylate）（E7389）、伊沙匹隆（ixabepilone）、氯尼達明（lonidamine）、馬索羅酚（masoprocol）、米托胍腙（mitoguanazone）、奧利默森（oblimersen）、舒林酸（sulindac）、睾內酯（testolactone）、噻唑呋林（tiazofurin）、mTOR抑制劑、PI3K抑制劑、Cdk4抑制劑、Akt抑制劑、Hsp90抑制劑、法呢基轉移酶抑制劑或芳香酶抑制劑（阿那曲唑來曲唑依西美坦（anastrozole letrozole exemestane））；xvi）Mek抑制劑；xvii）酪胺酸激酶抑制劑；xviii）c-Kit突變型抑制劑，xix）EGFR抑制劑、PD-1抑制劑，或xx）表觀遺傳調節劑。 Embodiment 45 of the present invention relates to the method of embodiment 44, wherein the one or more is one or more of the following: i) an alkylating agent selected from the group consisting of adozelesin, hexamethylmelamine ( altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin (cisplatin), cyclophosphamide, dacarb

(dacarbazine), estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven , lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine ( semustine), streptozocin, temozolomide, thiotepa and treosulfan; ii) antibiotics selected from bleomycin, dactinomycin , daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxanthen mitoxantrone, neocarzinostatin, pentostatin and plicamycin; iii) antimetabolites selected from the group consisting of: azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine ), 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) immunotherapeutic agents selected from PD-1 or PD-L1 inhibitors; v ) hormones or hormone antagonists selected from the group consisting of: enzalutamide, abiraterone, anastrozole, androgens, buseret Buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen and toremifene; vi) taxanes (taxane), which is selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) retinoid, which is selected From alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; viii) alkaloids selected from etoposide (etoposide), homoharringtonine (homoharringtonine), teniposide (teniposide), vinblastine (vinblastine), vincristine (vincristine), vindesine (vindesine) and vinorelbine (vinorelbine); ix) An anti-angiogenic agent selected from the group consisting of AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide and thalidomide; x ) topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl -10-Hydroxy-camptothecin) (SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan and 9-aminocamptothecin (9 -aminocamptothecin; xi) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib Lapatinib, Sorafenib , sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine) , vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; xii ) targeted signal transduction inhibitors selected from bortezomib, geldanamycin and rapamycin; xiii) biological response modifiers selected from imiquimod (imiquimod), interferon-alpha and interleukin-2; xiv) IDO inhibitors; and xv) chemotherapeutic agents selected from 3-AP (3-amino-2-hydroxyaldehyde thiohemizone) (3 -AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin- 1 (bryostatin-1), cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine ( lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibition drug, PI3K inhibitor, Cdk4 inhibitor, Akt inhibitor, Hsp90 inhibitor, farnesyl transferase inhibitor, or aromatase inhibitor (anastrozole letrozole exemestane); xvi) Mek inhibitor; xvii) tyrosine kinase inhibitor; xviii) c-Kit mutant inhibitor, xix) EGFR inhibitor, PD-1 inhibitor, or xx) epigenetic modulator.

本發明之實施例 46 係關於如實施例45之方法，其中該或更多種額外治療劑為PD-1或PD-L1抑制劑。 Embodiment 46 of the invention pertains to the method of embodiment 45, wherein the additional therapeutic agent(s) is a PD-1 or PD-L1 inhibitor.

本發明之實施例 47 係關於如實施例46之方法，其中該PD-1或PD-L1抑制劑為納武單抗（nivolumab）、帕博利珠單抗（pembrolizumab）、測米匹單抗（cemiplimab）、阿特珠單抗（atezolizumab）、阿維魯單抗（avelumab）或德瓦魯單抗（durvalumab）。 Embodiment 47 of the present invention relates to the method of embodiment 46, wherein the PD-1 or PD-L1 inhibitor is nivolumab (nivolumab), pembrolizumab (pembrolizumab), or mitrolizumab ( cemiplimab), atezolizumab, avelumab, or durvalumab.

本發明之實施例 47 （ a ） 係關於如實施例46之方法，其中該PD-1或PD-L1抑制劑為納武單抗、帕博利珠單抗、測米匹單抗、阿特珠單抗、阿維魯單抗、德瓦魯單抗或賽帕利單抗（zimberelimab）。 Embodiment 47 ( a ) of the present invention relates to the method of embodiment 46, wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, mepilimumab, atezolizumab mAb, avelumab, durvalumab, or zimberelimab.

本發明之實施例 48 係關於如實施例44之方法，其中該一或多種額外治療劑為PD-1抑制劑且該疾病或病況係大腸直腸癌。 Embodiment 48 of the invention relates to the method of embodiment 44, wherein the one or more additional therapeutic agents are PD-1 inhibitors and the disease or condition is colorectal cancer.

本發明之實施例 49 係關於如實施例44之方法，其包含投與第一及第二額外治療劑。 Embodiment 49 of the present invention pertains to the method of embodiment 44, comprising administering first and second additional therapeutic agents.

本發明之實施例 50 係關於如實施例49之方法，其中該第一額外治療劑為PD-1抑制劑，該第二額外治療劑為化學治療劑，且該疾病或病況係腺癌。 Embodiment 50 of the present invention relates to the method of embodiment 49, wherein the first additional therapeutic agent is a PD-1 inhibitor, the second additional therapeutic agent is a chemotherapeutic agent, and the disease or condition is adenocarcinoma.

本發明之實施例 50 （ a ） 係關於如實施例50之方法，其中該腺癌為轉移性胰管腺癌。 Embodiment 50 ( a ) of the present invention relates to the method of embodiment 50, wherein the adenocarcinoma is metastatic pancreatic duct adenocarcinoma.

在另一實施例中，本發明提供用於治療有需要之個體中之癌症之方法，其藉由向個體投與有效量之組合物，該組合物包括如本文中所描述之任何一或多種化合物與一或多種其他可有效治療癌症之療法或醫療程序之組合。其他療法或醫療程序包括適合的抗癌療法（例如，藥物療法、疫苗療法、基因療法、光動力療法）或醫療程序（例如，手術、輻射治療、高溫加熱、骨髓或幹細胞移植）。在一個實施例中，一或多種適合的抗癌療法或醫療程序係選自以下：使用化學治療劑（例如化學治療藥物）之治療、放射治療（例如x射線、.γ.-射線或電子、質子、中子或.α.粒子束）、高溫加熱（例如微波、超音波、射頻切除）、疫苗療法（例如AFP基因肝細胞癌疫苗、AFP腺病毒載體疫苗、AG-858、同種異體GM-CSF分泌乳癌疫苗、樹突狀細胞肽疫苗）、基因療法（例如Ad5CMV-p53載體、編碼MDA7之腺病毒載體、腺病毒5-腫瘤壞死因子α）、光動力療法（例如胺基乙醯丙酸、莫特沙芬鎦（motexatin lutetium））、手術或骨髓及幹細胞移植。VI. 套組 In another embodiment, the present invention provides methods for treating cancer in an individual in need thereof by administering to the individual an effective amount of a composition comprising any one or more as described herein A compound in combination with one or more other therapies or medical procedures that are effective in treating cancer. Other therapies or medical procedures include suitable anticancer therapies (eg, drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (eg, surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, one or more suitable anticancer therapies or medical procedures are selected from the group consisting of: treatment with chemotherapeutic agents (eg, chemotherapeutic drugs), radiation therapy (eg, x-rays, gamma-rays, or electrons, Proton, neutron or .alpha. particle beam), high temperature heating (e.g. microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM- CSF secreted breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g. Ad5CMV-p53 vector, adenovirus vector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g. aminolevulinic acid) , motexatin lutetium), surgery or bone marrow and stem cell transplantation. VI. Set

在另一態樣中，本發明提供套組，其包括如實施例 1-35 中之一者之化合物中的任一者中所描述之一或多種化合物或其醫藥學上可接受之鹽、氘代類似物、互變異構體或立體異構體，或如實施例 36-37 中之一者之醫藥組合物。在一些實施例中，化合物或組合物封裝於例如小瓶、瓶、燒瓶中，其可進一步封裝於例如盒子、封套或袋子內。化合物或組合物可由美國食品及藥物管理局（U.S. Food and Drug Administration）或類似管理機構批准用於向哺乳動物（例如人類）投與。可批准化合物或組合物用於向哺乳動物（例如人類）投與，以用於CD73介導之疾病或病況。本文中所描述之套組可包括化合物或組合物適合或批准用於向哺乳動物（例如人類）投與以用於CD73介導之疾病或病況之書面使用說明書及/或其他指示。化合物或組合物可以單位劑量或單次劑量形式封裝，例如單次劑量藥丸、膠囊或其類似物。VII. 結合分析 In another aspect, the present invention provides kits comprising one or more compounds or pharmaceutically acceptable salts thereof as described in any one of the compounds of one of embodiments 1-35 , A deuterated analog, tautomer or stereoisomer, or a pharmaceutical composition as in one of Examples 36-37 . In some embodiments, the compound or composition is packaged, eg, in a vial, bottle, flask, which may be further packaged, eg, within a box, envelope, or bag. A compound or composition may be approved by the US Food and Drug Administration or similar regulatory agency for administration to mammals (eg, humans). Compounds or compositions may be approved for administration to mammals (eg, humans) for CD73-mediated diseases or conditions. The kits described herein can include written instructions for use and/or other indications that a compound or composition is suitable or approved for administration to a mammal (eg, a human) for a CD73-mediated disease or condition. The compound or composition may be packaged in unit dose or single dose form, eg, single dose pills, capsules, or the like. VII. Binding Analysis

本發明之方法可以涉及能夠偵測化合物與目標分子之結合之分析。此類結合處於統計顯著水準且信賴水準為至少90%，或至少95、97、98、99%或更大的信賴水準（分析信號表示與目標分子之結合，亦即，區別於背景）。在一些實施例中，使用對照物區分目標結合與非特異性結合。已知多種用於不同目標類型之指示結合之分析且可以用於本發明。The methods of the present invention may involve assays capable of detecting the binding of a compound to a target molecule. Such binding is at a statistically significant level with a confidence level of at least 90%, or a confidence level of at least 95, 97, 98, 99% or greater (analyzed signal represents binding to the target molecule, ie, distinct from background). In some embodiments, a control is used to distinguish target binding from non-specific binding. A variety of assays for indicated binding of different target types are known and can be used in the present invention.

結合化合物可以藉由其對目標分子之活性之作用來表徵。因此，「低活性」化合物在標準條件下具有大於1 μM之抑制性濃度（IC₅₀ ）或有效濃度（EC₅₀ ）。「非常低活性」意謂在標準條件下之IC₅₀ 或EC₅₀ 大於100 μM。「極低活性」意謂在標準條件下之IC₅₀ 或EC₅₀ 大於1 mM。「中等活性」意謂在標準條件下之IC₅₀ 或EC₅₀ 為200 nM至1 μM。「中等高活性」意謂IC₅₀ 或EC₅₀ 為1 nM至200 nM。「高活性」意謂在標準條件下之IC₅₀ 或EC₅₀ 小於1 nM。IC₅₀ 或EC₅₀ 定義為相對於在不存在化合物時所觀測之活性範圍，損失或獲得所量測之目標分子（例如酶或其他蛋白質）活性之50%活性時之化合物濃度。可以使用一般熟習此項技術者已知之方法量測活性，例如藉由量測由於發生酶促反應而產生之任何可偵測產物或信號，或所量測之蛋白質之其他活性。A binding compound can be characterized by its effect on the activity of the target molecule. Thus, a "low activity" compound has an inhibitory concentration ( _IC50 ) or effective concentration ( _EC50 ) greater than 1 μM under standard conditions. "Very low activity" means an _IC50 or _EC50 greater than 100 μM under standard conditions. "Very low activity" means an _IC50 or _EC50 greater than 1 mM under standard conditions. "Moderately active" means an _IC50 or _EC50 of 200 nM to 1 μM under standard conditions. "Moderately high activity" means an _IC50 or _EC50 of 1 nM to 200 nM. "Highly active" means an _IC50 or _EC50 of less than 1 nM under standard conditions. _IC50 or _EC50 is defined as the concentration of compound at which 50% of the measured activity of the target molecule (eg, enzyme or other protein) is lost or gained relative to the range of activity observed in the absence of the compound. Activity can be measured using methods known to those of ordinary skill in the art, such as by measuring any detectable product or signal resulting from an enzymatic reaction, or other activity of the protein being measured.

關於結合分析之「背景信號」意謂在不存在結合於目標分子之測試化合物、分子骨架或配位體之情況下，在特定分析法之標準條件下記錄之信號。一般熟習此項技術者將認識到，存在公認的方法且可廣泛用於測定背景信號。"Background signal" in relation to a binding assay means the signal recorded under standard conditions for a particular assay in the absence of the test compound, molecular scaffold or ligand bound to the target molecule. Those of ordinary skill in the art will recognize that well-established methods exist and are widely available for determining background signal.

「標準差」意謂方差之平方根。方差為分佈之分佈程度之度量。其計算為每個數字與其平均值之平均平方偏差。舉例而言，對於數字1、2及3，平均值為2且方差為：

。表面電漿共振 "Standard deviation" means the square root of the variance. Variance is a measure of how spread out a distribution is. It is calculated as the mean squared deviation of each number from its mean. For example, for numbers 1, 2, and 3, the mean is 2 and the variance is:

. surface plasmon resonance

可以使用表面電漿共振量測結合參數，例如使用塗佈有固定結合組分之BIAcore^® 晶片（Biacore, Japan）。使用表面電漿共振表徵sFv或其他針對目標分子之配位體之間的反應之微觀締合及解離常數。此類方法通常描述於以引用之方式併入本文中之以下參考文獻中。Vely F.等人,（2000）《用於測試磷酸化肽-SH2結構域相互作用之BIAcore^® 分析（BIAcore^® analysis to test phosphopeptide-SH2 domain interactions）》, 《分子生物學方法（Methods in Molecular Biology.）》121:313-21；Liparoto等人,（1999）《介白素-2受體複合物之生物感測器分析（Biosensor analysis of the interleukin-2 receptor complex）》, 《分子識別雜誌（Journal of Molecular Recognition.）》12:316-21；Lipschultz等人,（2000）《使用表面電漿共振之複合物動力學之分析之實驗設計（Experimental design for analysis of complex kinetics using surface plasmon resonance）》, 《方法（Methods.）》20（3）:310-8；Malmqvist.,（1999）《BIACORE：用於表徵生物分子相互作用之親和力生物感測器（BIACORE: an affinity biosensor system for characterization of biomolecular interactions）》, 《生物化學學會學報（Biochemical Society Transactions）》, 27:335-40；Alfthan,（1998）《作為抗體工程改造中之工具之表面電漿共振生物感測器（Surface plasmon resonance biosensors as a tool in antibody engineering）》, 《生物感測器及生物電子學（Biosensors & Bioelectronics.）》13:653-63；Fivash等人,（1998）《用於巨分子相互相用之BIAcore（BIAcore for macromolecular interaction）》, 《生物技術之當前觀點（Current Opinion in Biotechnology.）》9:97-101；Price等人；（1998）《ISOBM TD-4研討會之總結報告：針對MUC1黏蛋白之56種單株抗體之分析（Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin）》。《腫瘤生物學（Tumour Biology）》19 增刊1：1-20；Malmqvist等人,（1997）《生物分子相互相用分析：用於蛋白質之功能性分析之親和力生物感測器技術（Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins）》, 《化學生物學之當前觀點（Current Opinion in Chemical Biology.）》1:378-83；O'Shannessy等人,（1996）《藉由生物感測器技術進行之配位體結合表徵中來自偽一階動力學狀態之偏差之解釋（Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology）》, 《分析生物化學（Analytical Biochemistry.）》236:275-83；Malmborg等人,（1995）《作為抗體工程改造中之工具之BIAcore（BIAcore as a tool in antibody engineering）》, 《免疫方法雜誌（Journal of Immunological Methods.）》183:7-13；Van Regenmortel,（1994）《使用生物感測器表徵重組蛋白質（Use of biosensors to characterize recombinant proteins）》, 《生物學標準化之發展（Developments in Biological Standardization.）》83:143-51；及O'Shannessy,（1994）《巨分子相互作用之動力學速率及均衡結合常數之測定：表面電漿共振文獻之評論（Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature）》, 《生物技術之當前觀點（Current Opinions in Biotechnology.）》5:65-71。Binding parameters can be measured using surface plasmon resonance, for example using ^BIAcore® wafers (Biacore, Japan) coated with immobilized binding components. Use surface plasmon resonance to characterize the microscopic association and dissociation constants of reactions between sFv or other ligands against target molecules. Such methods are generally described in the following references, which are incorporated herein by reference. Vely F. et al. (2000 ^{) BIAcore ® analysis} to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology .)"121:313-21; Liparoto et al., (1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition ( Journal of Molecular Recognition.)"12:316-21; Lipschultz et al., (2000) "Experimental design for analysis of complex kinetics using surface plasmon resonance" , "Methods." 20 (3): 310-8; Malmqvist., (1999) "BIACORE: an affinity biosensor system for characterization of biomolecular interactions interactions)", "Biochemical Society Transactions", 27:335-40; Alfthan, (1998) "Surface plasmon resonance biosensors as a tool in antibody engineering a tool in antibody engineering)", "Biosensors &Bioelectronics."13:653-63; Fivash et al., (1998) "BIAcore for macromolecular interactions (BIAcore for macromolecular interaction)", "Current Opinion in Biotechnology."9:97-101; Price et al; (1998) "ISOBM TD-4 Workshop Summary" Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19 Suppl 1:1-20; Malmqvist et al. (1997) Biomolecular interaction analysis: Biomolecular interaction analysis for functional analysis of proteins : affinity biosensor technologies for functional analysis of proteins)", "Current Opinion in Chemical Biology."1:378-83;O'Shannessy et al., (1996) "By Biosensors Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry Biochemistry.)"236:275-83; Malmborg et al., (1995) "BIAcore as a tool in antibody engineering", Journal of Immunological Methods. 183:7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83:143- 51; and O'Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature. surface plasmon resonance literature )”, Current Opinions in Biotechnology. 5:65-71.

BIAcore^® 使用表面電漿共振（SPR）之光學特性偵測結合於位於金/玻璃感測器晶片界面之表面上的聚葡萄糖基質（一種聚葡萄糖生物感測器基質）之蛋白質濃度之變化。簡言之，蛋白質以已知濃度共價結合於聚葡萄糖基質且經由聚葡萄糖基質注射蛋白質之配位體。引導至感測器晶片表面之相對側上之近紅外光被反射且亦誘導金薄膜中之消散波，其又引起特定角（稱為共振角）處反射光之強度坑。若感測器晶片表面之折射率改變（例如藉由結合於結合蛋白質之配位體），則共振角度發生偏移。此可以量測此角度偏移且表示為共振單位（RU），使得1000 RU等效於1 ng/mm² 之表面蛋白質濃度變化。沿感測器圖譜之y軸相對於時間顯示此等變化，該感測器圖譜描繪任何生物反應之關聯及解離。高通量篩選（ HTS ）分析 BIAcore ^® uses the optical properties of surface plasmon resonance (SPR) to detect changes in the concentration of proteins bound to a polydextrose matrix, a polydextrose biosensor matrix, on the surface at the gold/glass sensor wafer interface. Briefly, proteins are covalently bound to a polydextrose matrix at known concentrations and the ligands of the proteins are injected through the polydextrose matrix. The near-infrared light directed onto the opposite side of the sensor wafer surface is reflected and also induces evanescent waves in the gold film, which in turn cause intensity pits of the reflected light at specific angles (called resonance angles). If the refractive index of the sensor wafer surface changes (eg by binding to protein-bound ligands), the resonance angle shifts. This angular shift can be measured and expressed as resonance units (RU) such that 1000 RU is equivalent to a 1 ng/mm ² change in surface protein concentration. These changes are shown versus time along the y-axis of the sensor map, which depicts the association and dissociation of any biological response. High Throughput Screening ( HTS ) Analysis

HTS通常使用自動分析針對所需活性搜索大量化合物。通常，使用HTS分析法，藉由篩選對特定酶或分子起作用之化學物質來尋找新的藥物。舉例而言，若化學物質不活化酶，則可證實其可有效防止細胞中引起疾病之過程。高通量方法使得研究人員能夠使用機器操作系統及自動結果分析，極快速地針對各目標分子分析數千種不同的化學物質。HTS typically searches large numbers of compounds for the desired activity using automated analysis. Typically, HTS assays are used to find new drugs by screening chemicals that act on specific enzymes or molecules. For example, if a chemical does not activate an enzyme, it may prove effective in preventing disease-causing processes in cells. The high-throughput method enables researchers to analyze thousands of different chemicals for each target molecule extremely quickly, using machine operating systems and automated results analysis.

如本文所使用，「高通量篩選」或「HTS」係指大量化合物（庫）之快速活體外篩選；通常數萬至數十萬種化合物，使用機器人篩選分析法。超高通量篩選（uHTS）通常係指加速至超過每天100,000次測試之高通量篩選。As used herein, "high-throughput screening" or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries); typically tens of thousands to hundreds of thousands of compounds, using robotic screening assays. Ultra-high-throughput screening (uHTS) generally refers to high-throughput screening accelerated to more than 100,000 tests per day.

為實現高通量篩選，有利的係，在多容器載體或平台上裝載樣本。多容器載體有助於同時量測複數種候選化合物之反應。可使用多孔微板作為載體。此類多孔微板及其用於多種分析法中之方法皆為此項技術中已知且可商購的。To achieve high-throughput screening, it is advantageous to load samples on a multi-container carrier or platform. The multi-container carrier facilitates the simultaneous measurement of reactions of multiple candidate compounds. Multiwell microplates can be used as supports. Such multiwell microplates and methods for their use in various assays are known in the art and are commercially available.

篩檢分析法可包括用於校準及證實正確操控分析之組分之目的之對照。通常包括空白孔，其含有所有反應物，但不含有化學庫之成員。作為另一實例，可將尋求調節劑之酶之已知抑制劑（或活化劑）與分析之一種樣本一起培育，且使用所得酶活性之降低（或增加）作為比較物或對照物。將瞭解，調節劑亦可與酶活化劑或抑制劑組合，以尋找抑制由存在已知的酶調節劑而以其他方式引起之酶活化或遏制。在篩選分析法期間量測酶促及結合反應 Screening assays may include controls for the purpose of calibration and verification of correct manipulation of the components of the assay. Blank wells are typically included, containing all reactants, but no members of the chemical library. As another example, a known inhibitor (or activator) of the enzyme for which the modulator is sought can be incubated with a sample of the assay and the resulting decrease (or increase) in enzyme activity used as a comparator or control. It will be appreciated that modulators may also be combined with enzyme activators or inhibitors in order to seek to inhibit enzyme activation or repression otherwise caused by the presence of known enzyme modulators. Measure enzymatic and binding reactions during screening assays

用於量測酶促及結合反應之進程之技術（例如在多容器載體中）為此項技術中已知的且包括（但不限於）以下。Techniques for measuring the progress of enzymatic and binding reactions (eg, in multi-container vectors) are known in the art and include, but are not limited to, the following.

分光光度法及螢光分光光度分析為本領域中熟知的。此類分析法之實例包括使用用於偵測過氧化物之比色分析法，如Gordon, A. J.及Ford, R. A.,（1972）《化學工作指南：實際資料、技術及參考文獻之手冊（The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References）》, John Wiley and Sons, N.Y., 第437頁中所描述。Spectrophotometry and spectrofluorimetric analysis are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, such as Gordon, AJ and Ford, RA, (1972) The Chemist's Guide to Working in Chemistry: A Handbook of Practical Information, Techniques, and References. Companion: A Handbook Of Practical Data, Techniques, And References), John Wiley and Sons, NY, p. 437.

螢光光譜測定法可用於監測反應產物之產生。螢光方法通常比吸收方法更敏感。螢光探針之用途為熟習此項技術者所熟知的。關於評述，參見Bashford等人,（1987）《分光光度法及螢光分光光度法：實用方法（Spectrophotometry and Spectrofluorometry: A Practical Approach）》, 第91-114頁, IRL Press Ltd.；及Bell,（1981）《生物化學中之光譜學（Spectroscopy In Biochemistry）》, 第I卷, 第155-194頁, CRC Press。Fluorescence spectrometry can be used to monitor the production of reaction products. Fluorescence methods are generally more sensitive than absorption methods. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al. (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd.; and Bell, ( 1981) Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press.

在螢光分光光度方法中，酶曝露於在由目標酶處理時可改變其內源螢光之底物。通常，底物為非螢光的且經由一或多個反應轉化為螢光團。作為非限制性實例，可以使用Amplex^® Red試劑（Molecular Probes, Eugene, OR）偵測SMase活性。為使用Amplex^® Red量測神經磷脂酶活性，進行以下反應。第一，SMase使鞘磷脂水解以產生神經醯胺及磷酸膽鹼。第二，鹼性磷酸酶使磷酸膽鹼水解以產生膽鹼。第三，膽鹼由膽鹼氧化酶氧化為甜菜鹼。最終，在存在辣根過氧化酶之情況下，H₂ O₂ 與Amplex^® Red反應以產生螢光產物試鹵靈（Resorufin）且使用光譜螢光量測術偵測來自其之信號。In a spectrofluorometric method, an enzyme is exposed to a substrate that alters its endogenous fluorescence upon treatment by the target enzyme. Typically, the substrate is non-fluorescent and converted to a fluorophore via one or more reactions. As a non-limiting example, SMase activity can be detected using ^Amplex® Red reagent (Molecular Probes, Eugene, OR). To measure sphingomyelinase activity using Amplex ^® Red, the following reactions were performed. First, SMase hydrolyzes sphingomyelin to produce ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, choline is oxidized to betaine by choline oxidase. Finally, ^H2O2 reacts with _Amplex® Red in the presence of horseradish peroxidase to produce the fluorescent product _Resorufin and the signal therefrom is detected using spectrofluorometry.

螢光偏振（FP）係基於在結合於較大分子（諸如受體蛋白質）時進行的螢光團之分子旋轉速度之降低，考慮由結合之配位體進行之偏振螢光發射。藉由在藉由平面偏振光激勵之後，量測螢光團發射之豎直及水平組分來憑經驗測定FP。當螢光團之分子旋轉降低時，偏振發射增加。螢光團在結合於較大分子（亦即，受體）時產生較大偏振信號，減緩螢光團之分子旋轉。偏振信號之量值以定量方式與螢光配位體結合程度相關。因此，「結合」信號之偏振視高親和力結合之維護而定。Fluorescence polarization (FP) is based on the reduction in the molecular rotational speed of the fluorophore upon binding to larger molecules such as receptor proteins, taking into account polarized fluorescence emission by bound ligands. FP was determined empirically by measuring the vertical and horizontal components of the fluorophore emission after excitation by plane polarized light. Polarized emission increases as the molecular rotation of the fluorophore decreases. Fluorophores generate larger polarized signals when bound to larger molecules (ie, receptors), slowing down the molecular rotation of the fluorophore. The magnitude of the polarized signal correlates in a quantitative manner with the degree of binding of the fluorescent ligand. Thus, the polarization of the "binding" signal depends on the maintenance of high affinity binding.

FP為均質技術且反應為極快速的，耗費數秒至數分鐘達到平衡。試劑為穩定的且可製備大批量，產生高再現性。由於此等特性，已證實FP為高度可自動化的，通常用單一、預先混合、示蹤劑-受體試劑，用單次培育進行。關於評述，參見Owicki等人,（1997）, 《高通量篩選中螢光偏振分析法之應用（Application of Fluorescence Polarization Assays in High-Throughput Screening）》, 《基因工程改造新聞（Genetic Engineering News）》, 17:27。FP is a homogeneous technique and the reaction is extremely fast, taking seconds to minutes to equilibrate. The reagents are stable and can be prepared in large batches, resulting in high reproducibility. Because of these properties, FP has proven to be highly automatable, typically performed with a single, pre-mixed, tracer-receptor reagent, with a single incubation. For a review, see Owicki et al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News , 17:27.

FP由於其讀取與發射強度無關（Checovich, W. J.等人,（1995）《自然（Nature）》 375:254-256；Dandliker, W. B.等人,（1981）《酶學方法（Methods in Enzymology）》74:3-28）且因此對存在可淬滅螢光發射之有色化合物不敏感而為尤其理想的。FP及FRET（參見下文）良好適用於鑑別可阻斷鞘脂受體與其配位體之間的相互作用之化合物。參見例如Parker等人,（2000）《使用螢光偏振之高通量篩選分析法之發展：細胞核受體-配位體結合及激酶/磷酸酶分析法（Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays）》, 《生物分子篩選雜誌（J Biomol Screen）》5:77-88。FP is not related to emission intensity due to its readout (Checovich, WJ et al. (1995) Nature 375:254-256; Dandliker, WB et al. (1981) Methods in Enzymology). 74:3-28) and is therefore particularly desirable for being insensitive to the presence of colored compounds that can quench fluorescence emission. FP and FRET (see below) are well suited for identifying compounds that block the interaction between sphingolipid receptors and their ligands. See eg, Parker et al. (2000) Development of high throughput screening assays using fluorescence polarization: Nuclear receptor-ligand binding and kinase/phosphatase assays. nuclear receptor-ligand-binding and kinase/phosphatase assays), J Biomol Screen 5:77-88.

可用於FP分析法中之來源於鞘脂之螢光團為可商購的。舉例而言，Molecular Probes（Eugene, OR）當前售賣鞘磷脂及一種神經醯胺螢光團。其分別為N-(4,4-二氟-5,7-二甲基-4-硼-3a,4a-二氮-s-二環戊二烯并苯-3-戊醯基)鞘胺醯基磷酸膽鹼（BODIPY® FL C5-鞘磷脂）；N-(4,4-二氟-5,7-二甲基-4-硼-3a,4a-二氮-s-二環戊二烯并苯-3-十二醯基）鞘胺醯基磷酸膽鹼（BODIPY® FL C12-鞘磷脂）；及N-(4,4-二氟-5,7-二甲基-4-硼-3a,4a-二氮-s-二環戊二烯并苯-3-戊醯基)神經鞘胺醇（BODIPY^® FL C5-神經醯胺）。美國專利第4,150,949號（用於慶大黴素（gentamicin）之免疫分析）揭示螢光素標記之慶大黴素，包括螢光素硫胺基甲醯基慶大黴素。可使用熟習此項技術者熟知之方法製備額外螢光團。Sphingolipid-derived fluorophores useful in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and a ceramide fluorophore. which are N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-dicyclopentadienacene-3-pentanoyl)sphingamine, respectively Acylphosphorylcholine (BODIPY® FL C5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-dicyclopentanedi Enacene-3-dodecanoyl)sphingomyelinylphosphocholine (BODIPY® FL C12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-boron -3a,4a-diaza-s-dicyclopentadienacene-3-pentanoyl)sphingosine (BODIPY ^® FL C5-ceramide). US Patent No. 4,150,949 (for immunoassays of gentamicin) discloses luciferin-labeled gentamicins, including luciferin thiamidocarboxygentamicin. Additional fluorophores can be prepared using methods well known to those skilled in the art.

例示性正常及偏振螢光讀取器包括POLARION^® 螢光偏振系統（Tecan AG, Hombrechtikon, Switzerland）。可使用用於其他分析法之通用多孔板讀取器，諸如VERSAMAX^® 讀取器及SPECTRAMAX^® 多孔板分光光度計（皆來自分子裝置（Molecular Devices））。Exemplary normal and polarized fluorescence readers include the ^POLARION® fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). Universal multiwell plate readers for other assays can be used, such as the ^VERSAMAX® reader and the ^SPECTRAMAX® multiwell plate spectrophotometer (both from Molecular Devices).

螢光共振能量轉移（FRET）係另一種適用於偵測相互作用之分析法且已被描述。參見例如Heim等人,（1996）《當前生物學（Curr. Biol.）》 6:178-182；Mitra等人,（1996）《基因（Gene）》173:13-17；及Selvin等人,（1995）《酶學方法（Meth. Enzymol.）》246:300-345。FRET偵測具有已知激勵及發射波長之極靠近的兩種螢光物質之間之能量轉移。作為實例，蛋白質可以表示為具有綠色螢光蛋白質（GFP）之融合蛋白質。當兩個螢光蛋白質靠近時，諸如當蛋白質與目標分子特異性相互作用時，共振能量可以自一個激發分子轉移至另一個激發分子。因此，樣本之發射光譜偏移，其可由螢光計（諸如fMAX多孔螢光計（Molecular Devices, Sunnyvale Calif.））量測。Fluorescence resonance energy transfer (FRET) is another assay suitable for detecting interactions and has been described. See, eg, Heim et al. (1996) Curr. Biol. 6:178-182; Mitra et al. (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects energy transfer between two fluorescent species with known excitation and emission wavelengths that are in close proximity. As an example, a protein can be represented as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are brought into close proximity, such as when the proteins interact specifically with a target molecule, resonance energy can be transferred from one excitation molecule to the other. Thus, the emission spectrum of the sample is shifted, which can be measured by a fluorometer such as an fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

閃爍近接分析法（SPA）為尤其適用於偵測與目標分子之相互相用之分析法。SPA廣泛用於醫藥學工業中且已被描述（Hanselman等人,（1997）《脂質研究雜誌（J. Lipid Res.）》38:2365-2373；Kahl等人,（1996）《分析生物化學（Anal. Biochem.）》243:282-283；Undenfriend等人,（1987）《分析生物化學》161:494-500）。亦參見美國專利第4,626,513號及第4,568,649號及歐洲專利第0,154,734號。一種市售系統使用經FLASHPLATE^® 閃爍體塗佈之板（NEN Life Science Products, Boston, MA）。Scintillation Proximity Analysis (SPA) is an analysis method particularly suitable for detecting interactions with target molecules. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al. (1997) J. Lipid Res. 38:2365-2373; Kahl et al. (1996) Analytical Biochemistry ( Anal. Biochem. 243:282-283; Undenfriend et al. (1987) Analytical Biochem 161:494-500). See also US Patent Nos. 4,626,513 and 4,568,649 and European Patent No. 0,154,734. A commercially available system uses ^FLASHPLATE® scintillator-coated plates (NEN Life Science Products, Boston, MA).

目標分子可以藉由多種熟知手段結合至閃爍體板。可使用閃爍體板，其經衍生以結合至融合蛋白質，諸如GST、His6或Flag融合蛋白質。當目標分子為蛋白質複合物或多聚體時，一個蛋白質或子單元可首先連接至板，隨後在結合條件下添加複合物之另一組分，產生結合之複合物。The target molecule can be bound to the scintillator plate by a variety of well-known means. Scintillation plates can be used, which are derivatized to bind to fusion proteins, such as GST, His6, or Flag fusion proteins. When the target molecule is a protein complex or multimer, one protein or subunit can be attached to the plate first, followed by the addition of another component of the complex under binding conditions, resulting in a bound complex.

在典型SPA分析法中，表現池中之基因產物將經放射性標記且添加至孔中，且使其與固相相互作用，該固相係塗佈於孔中之經固定之目標分子及閃爍體。可以立即量測分析法或使其達到平衡。以任一種方式，當放射性標記變得足夠靠近閃爍體塗層時，其產生可由裝置（諸如TOPCOUNT NXT^® 微板閃爍計數器（Packard BioScience Co., Meriden Conn.））偵測之信號。若經放射性標記之表現產物結合至目標分子，則放射性標記保持靠近閃爍體足夠長時間以產生可偵測信號。In a typical SPA assay, the gene product in the expression cell would be radiolabeled and added to the well and allowed to interact with the solid phase, which is the immobilized target molecule and scintillator coated in the well . Analytical methods can be measured immediately or allowed to equilibrate. Either way, when the radiolabel comes close enough to the scintillator coating, it produces a signal that can be detected by a device such as a TOPCOUNT ^NXT® microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If the radiolabeled expression product binds to the target molecule, the radiolabel remains near the scintillator long enough to generate a detectable signal.

相比之下，未結合至目標分子或僅短暫結合之經標記之蛋白質將不會保持靠近閃爍體足夠長時間以產生高於背景之信號。由隨機布朗運動（random Brownian motion）引起之在閃爍體附近耗費之任何時間亦將不產生大量信號。同樣，可能存在在表現步驟期間使用之殘餘的未合併之放射性標記，但將不產生顯著信號，因為其將在溶液中而非與目標分子相互作用。因此，此等非結合相互作用將引起可以數學方式移除之某一水準之背景信號。若獲得過多的信號，則可向分析板中直接添加鹽或其他調節劑直至獲得所需特異性（Nichols等人,（1998）《分析生物化學》257:112-119）。通用合成 In contrast, a labeled protein that does not bind to the target molecule or that binds only briefly will not remain near the scintillator long enough to generate a signal above background. Any time spent in the vicinity of the scintillator caused by random Brownian motion will also not generate a significant amount of signal. Also, there may be residual unincorporated radiolabel used during the expression step, but will not produce a significant signal since it will be in solution rather than interacting with the target molecule. Thus, these non-binding interactions will give rise to some level of background signal that can be mathematically removed. If excessive signal is obtained, salts or other modifiers can be added directly to the assay plate until the desired specificity is obtained (Nichols et al. (1998) Analytical Biochemistry 257:112-119). Universal synthesis

化合物可使用本文所揭示之方法及其常規修改（根據本文中之揭示內容將顯而易見）及此項技術中熟知之方法來製備。除本文中之教示以外，亦可使用習知及熟知之合成方法。本文所描述之典型化合物之合成可如以下實例中所描述來實現。若可獲得，則試劑可商購，例如購自西格瑪奧德里奇（Sigma Aldrich）或其他化學供應商。Compounds can be prepared using the methods disclosed herein and routine modifications thereof (as will be apparent from the disclosure herein) and methods well known in the art. In addition to the teachings herein, well-known and well-known synthetic methods may also be used. The synthesis of typical compounds described herein can be accomplished as described in the following examples. If available, reagents are commercially available, eg, from Sigma Aldrich or other chemical suppliers.

本發明之化合物可以使用例如以下通用方法及程序來由可容易獲得之起始物質製備。應瞭解，除非另外陳述，否則當給出典型或較佳的製程條件（亦即，反應溫度、時間、反應物之莫耳比、溶劑、壓力等）時，亦可使用其他製程條件。最佳反應條件可隨所使用之特定反應物或溶劑而變化，但此類條件可由熟習此項技術者藉由常規最佳化程序確定。Compounds of the present invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that when typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used, unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

此外，如熟習此項技術者將顯而易知，可能必需習知保護基來防止某些官能基經歷非所需反應。用於各種官能基之適合的保護基以及用於保護特定官能基及使特定官能基去保護之適合的條件為此項技術中所熟知。舉例而言，大量保護基描述於Wuts, P. G. M., Greene, T. W.& Greene, T. W.（2006）《有機合成中之格林保護基（Greene's protective groups in organic synthesis.）》Hoboken, N.J., Wiley-Interscience及其中引用之參考文獻中。Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, a number of protecting groups are described in Wuts, PGM, Greene, TW & Greene, TW (2006) Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and in in the cited references.

此外，本發明之化合物可含有一或多個不對稱或對掌性中心。因此，必要時，此類化合物可以製備或分離為純立體異構體，亦即，製備或分離為個別對映異構體或非對映異構體，或製備或分離為立體異構體增濃混合物。除非另外指示，否則所有此類立體異構體（及增濃混合物）均包括於本發明之範疇內。純立體異構體（或增濃混合物）可使用例如此項技術中熟知之光學活性起始材料或立體選擇性試劑來製備。或者，可以使用例如對掌性管柱層析、超臨界流體層析、對掌性晶種、對掌性解析劑及其類似方法分離此類化合物之外消旋混合物。In addition, the compounds of the present invention may contain one or more asymmetric or chiral centers. Accordingly, such compounds may be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as increased stereoisomers, if desired. Concentrated mixture. All such stereoisomers (and enriched mixtures) are included within the scope of this invention unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be isolated using methods such as chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, and the like.

用於以下反應之起始材料為通常已知的化合物或可藉由已知程序或其顯而易知的改良來製備。舉例而言，許多起始物質可自商業供應商獲得，諸如奧德里奇化學公司（Aldrich Chemical Co.）（美國威斯康辛州之密爾沃基（Milwaukee, Wisconsin, USA））、巴亨（Bachem）（美國加利福尼亞州之托蘭斯（Torrance, California, USA））、Emka-Chemce或西格瑪（Sigma）（美國密蘇里州之聖路易斯（St. Louis, Missouri, USA））。其他起始物質可藉由描述於標準參考文本中之程序或其明顯修改來製備，該等標準參考文本諸如《費斯爾及費斯爾之有機合成試劑（Fieser and Fieser's Reagents for Organic Synthesis）》, 第1-15卷（約翰·威利父子出版公司（John Wiley, and Sons, 1991））；《羅德之碳化合物化學（Rodd's Chemistry of Carbon Compounds）》, 第1-5卷及增刊（愛思唯爾科學出版社（Elsevier Science Publishers）, 1989）；《有機反應（organic Reactions）》, 第1-40卷（約翰·威利父子出版公司，1991）；《馬奇之有機化學（March's Advanced Organic Chemistry）》,（約翰·威利父子出版公司, 第5版, 2001），及《拉洛克之全面有機轉換（Larock's Comprehensive Organic Transformations）》（VCH出版社公司（VCH Publishers Inc.）, 1989）。The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (California, USA) Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, or obvious modifications thereof , Volumes 1-15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Lodd's Chemistry of Carbon Compounds) Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley & Sons, 1991); March's Advanced Organic Chemistry Organic Chemistry, (John Wiley & Sons, 5th ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) .

亦應理解，在任一個流程中，添加任何取代基可引起產生多種異構產物（包括（但不限於）對映異構體或一或多種非對映異構體），其中之任一者或全部可使用習知技術分離及純化。當需要對映異構純或增濃化合物時，對掌性層析及/或對映異構純或增濃起始物質可如習知地用於此項技術或如實例中所描述地利用。It is also understood that in either scheme, the addition of any substituents can result in the production of multiple isomeric products (including but not limited to enantiomers or one or more diastereomers), any of which or All can be isolated and purified using known techniques. When enantiomerically pure or enriched compounds are desired, chiral chromatography and/or enantiomerically pure or enriched starting materials can be used as known in the art or utilized as described in the Examples .

本發明之化合物可根據通用反應流程及/或下文所描述之實例合成。可藉由用具有類似結構之其他材料取代起始物質以產生相應產物來改變通用流程。所需產物之結構將通常使熟習此項技術者顯而易見所需起始物質。The compounds of the present invention can be synthesized according to the general reaction schemes and/or the examples described below. The general scheme can be modified by substituting other materials of similar structure for the starting materials to yield the corresponding products. The structure of the desired product will generally make the desired starting materials apparent to those skilled in the art.

流程1提供用於合成本文中所提供之化合物（例如式I化合物）之例示性合成途徑。通常藉由首先提供核心式X（a）或X（d）且隨後使用適合的條件（例如共軛加成；碳酸鹽、胺基甲酸酯或尿素形成；或交叉偶合）連接所需取代基來製備式I化合物或本文中所揭示之其他化學式或化合物。Scheme 1 provides an exemplary synthetic route for the synthesis of compounds provided herein, such as compounds of Formula I. The desired substituents are typically attached by first providing the core formula X(a) or X(d) and then using suitable conditions (eg, conjugate addition; carbonate, carbamate or urea formation; or cross-coupling) to prepare compounds of formula I or other formulae or compounds disclosed herein.

在一些實施例中，根據流程1進行式I化合物之合成。流程 1

In some embodiments, the synthesis of compounds of formula I is performed according to Scheme 1. Process 1

在流程1中，A、E、G、L、R¹ 、R² 及R³ 係如式I中所定義。在流程1中，式X（a）之化合物轉化成式X（b）之化合物。式X（b）之化合物隨後可視情況經由式X（c）轉化為式X（d）之化合物，其可轉化成式I之化合物。A¹ 、E¹ .、E¹¹ .、G¹ 、L¹ 、L² 、L¹¹ 、P¹ 、R¹⁵ 、R²¹ 、R³¹ 、Z¹ 及Z² 如下文所描述。In Scheme ¹ , A, E, G, L, R1, R2 and ^R3 are as defined in ^formula I. In Scheme 1, compounds of formula X(a) are converted to compounds of formula X(b). Compounds of formula X(b) can then optionally be converted via formula X(c) to compounds of formula X(d), which can be converted to compounds of formula I. A ¹ , E ¹ ., E ¹¹ ., G ¹ , L ¹ , L ² , L ¹¹ , P ¹ , R ¹⁵ , R ²¹ , R ³¹ , Z ¹ and Z ² are described below.

在流程1中，Z¹ 及Z² 中之每一者獨立地為脫離基，例如鹵化物或適合的偶合搭配物，或Z² 為R²¹ 。舉例而言，Z¹ 及/或Z² 可為氯化物或溴化物。作為偶合搭配物，Z¹ 或Z² 可例如藉由諸如鋅金屬之還原鋅試劑原位活化。式X（a）之化合物可與化合物101 在共軛加成反應條件下反應。 ^In Scheme ¹ , each of Z1 and Z2 is independently a leaving group, such as a halide or a suitable coupling ^partner , or Z2 is ^R21 . For example, Z ¹ and/or Z ² can be chloride or bromide. As ^a coupling ^partner , Z1 or Z2 can be activated in situ, eg, by reducing zinc reagents such as zinc metal. Compounds of formula X(a) can be reacted with compound 101 under conjugate addition reaction conditions.

在流程1中，P¹ 為H、R¹⁵ 或N-保護基。舉例而言，P¹ 可為與母體結構形成胺縮醛或醯胺之N-保護基（例如，P¹ 可為四氫哌喃，諸如四氫-2H-哌喃-2-基（「THP」））。在P¹ 為H之情況下，R¹⁵ 可藉由習知方式添加，例如藉由將母體結構親核加成至諸如初始鹵化物之鹵化物中（例如，其中R¹⁵ 為R¹ 之經保護前驅物，諸如2-(2-溴乙氧基)四氫-2H-哌喃)。其中P¹ 包含哌喃，哌喃可藉由習知哌喃去保護條件移除，例如如本文所描述或如此項技術中已知。在P¹ 不為H之情況下，P¹ 可藉由習知方式，例如藉由根據本文所描述或此項技術中已知之方法的保護基化學方法添加。舉例而言，P¹ 可藉由將母體結構酸催化加成至二氫-2H -哌喃中來添加。In Scheme 1, P ¹ is H, R ¹⁵ or an N-protecting group. For example, P ¹ can be an N-protecting group that forms an amine acetal or amide with the parent structure (eg, P ¹ can be a tetrahydropyran, such as tetrahydro-2H-pyran-2-yl ("THP ”)). Where P1 is H, ^R15 can be added by conventional means, such as by nucleophilic addition of the parent structure to ^a halide such as the initial halide (eg, where ^R15 is ^a protected R15 Precursors such as 2-(2-bromoethoxy)tetrahydro-2H-pyran). wherein P1 comprises ^a piperan, which can be removed by conventional piperan deprotection conditions, eg, as described herein or known in the art. ^In cases where P1 is not H, ^P1 can be added by conventional means, eg, by protecting group chemistry according to methods described herein or known in the art. For example, P1 can be added by acid ^- catalyzed addition of the parent structure to dihydro- 2H -pyran.

在流程1中，R¹⁵ 為R¹ 或R¹ 之衍生物，諸如R¹ 之經保護衍生物。在一些實施例中，R¹⁵ 為R¹ 之經羥基保護之衍生物。舉例而言，R¹ 之經羥基保護之衍生物可包括矽烷基醚、乙酸酯、苯甲基、苯甲醯基、縮丙酮化合物或四氫哌喃基衍生物（例如其中R¹ 為乙-2-醇，R¹⁵ 可為2-((四氫-2H-哌喃-2-基)氧基)乙基)。在一些實施例中，R¹⁵ 包含對應於R¹ 處之二醇之經保護之二醇（例如其中R¹ 包含鄰二醇，R¹⁵ 可包含二氧戊環）。In Scheme ¹ , ^R15 is R1 or ^a derivative of R1, such as ^a protected derivative of R1. In some embodiments, R ¹⁵ is a hydroxy-protected derivative of R ¹ . For example, hydroxyl ^- protected derivatives of R can include silyl ether, acetate, benzyl, benzyl, acetonide, or tetrahydropyranyl derivatives (eg, wherein R is ethyl ⁾ -2-ol, R ¹⁵ can be 2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl). In some embodiments, R ¹⁵ comprises a protected diol corresponding to the diol at R ¹ (eg, where R ¹ comprises an vicinal diol, R ¹⁵ may comprise dioxolane).

在流程1中，A¹ 為A或其衍生物。A¹ 處之A之衍生物可進一步包括取代基，A可自該取代基藉由氧化、還原及/或保護衍生（例如A¹ 可包含其中A包含醯胺之氰基取代基）。舉例而言，A¹ 可為吡咯啶-1-基，諸如(R)-3-羥基吡咯啶-1-基或(3S,4S)-3-羥基-4-氟吡咯啶-1-基。In Scheme 1, A ¹ is A or a derivative thereof. Derivatives of ^A at A1 may further comprise substituents from which A may be derived by oxidation, reduction and/or protection (eg A1 may comprise ^a cyano substituent wherein A comprises amide). For example, A ¹ can be pyrrolidin-1-yl, such as (R)-3-hydroxypyrrolidin-1-yl or (3S,4S)-3-hydroxy-4-fluoropyrrolidin-1-yl.

在流程1中，E¹ 為E或其衍生物，或E¹ 可為H。E¹ 處之E之衍生物可包含脫離基或適合的偶合搭配物（例如E¹ 可包含諸如溴或碘之鹵基）。E¹ 處之E之衍生物可進一步包括取代基，E可自該取代基藉由氧化、還原及/或保護衍生（例如E¹ 可包含其中E包含醯胺之氰基取代基）。式X（b）之化合物可與化合物102 或化合物104 在如本文所描述或此項技術中已知之親核的芳族取代條件或銅偶合條件下反應。在一些實施例中，E¹ 可包含苯基、嗒

基-4-基、嘧啶基-4-基、嘧啶基-6-基、吡啶基、吡啶基-3-基或吡啶基-4-基。在一些實施例中，L¹ -E¹¹ 為4-溴吡啶-2-基、4-溴-5-氯-2-氟-吡啶、3-溴-5-碘-吡啶、1-溴-3-碘苯、5-溴-3-氯-嗒

或4,6-二氯嘧啶。當化合物X（b）直接轉化成式X（d）時，式X（b）可與化合物104 反應。在此類實施例中，G¹ -L² -E¹¹ 可為4-(2-氟-4-吡啶基)-3,5-二甲基-異

唑或4-(6-氯嗒

-4-基)-3,5-二甲基-異

唑。In Scheme ¹ , E1 is E or ^a derivative thereof, or E1 can be H. Derivatives of E at E ¹ may contain a leaving group or a suitable coupling partner (eg, E ¹ may contain a halo group such as bromine or iodine). Derivatives of E at E ¹ may further include substituents from which E may be derived by oxidation, reduction and/or protection (eg E ¹ may include a cyano substituent wherein E includes amide). Compounds of formula X(b) can be reacted with compound 102 or compound 104 under nucleophilic aromatic substitution conditions or copper coupling conditions as described herein or known in the art. In some embodiments, E ¹ may comprise phenyl, pyridine

yl-4-yl, pyrimidinyl-4-yl, pyrimidinyl-6-yl, pyridyl, pyridin-3-yl or pyridyl-4-yl. In some embodiments, L ¹ -E ¹¹ is 4-bromopyridin-2-yl, 4-bromo-5-chloro-2-fluoro-pyridine, 3-bromo-5-iodo-pyridine, 1-bromo-3 - iodobenzene, 5-bromo-3-chloro-d

or 4,6-dichloropyrimidine. When compound X(b) is directly converted to formula X(d), formula X(b) can be reacted with compound 104 . In such embodiments, G ¹ -L ² -E ¹¹ can be 4-(2-fluoro-4-pyridyl)-3,5-dimethyl-iso

oxazole or 4-(6-chloridate

-4-yl)-3,5-dimethyl-iso

azoles.

在流程1中，E¹¹ 為適用於藉由與化合物102 或化合物104 反應將E¹ 附加至式X（b）之母體結構的E¹ 之衍生物。舉例而言，式X（b）之化合物可與化合物102 或化合物104 在親核置換條件（例如，親核芳族取代條件）下反應。In Scheme ¹ , ^E11 is ^a derivative of E1 suitable for attaching E1 to the parent structure of formula X(b) by reaction with compound 102 or compound 104 . For example, a compound of formula X(b) can be reacted with compound 102 or compound 104 under nucleophilic displacement conditions (eg, nucleophilic aromatic substitution conditions).

在流程1中，L¹ 及L² 中之每一者獨立地為L之一部分或衍生物，或L¹ 可為H，或L² 可為L。L在L¹ 處之部分或衍生物可包括L之剩餘部分或G¹ 之連接點處的氫原子（例如，其中L包括如連接至母體結構之氧原子或氮原子，A¹ -L¹ 可為對應羥基、胺或-C(O)NH₂ ）。L在L¹ 處之部分或衍生物可包含G¹ 之連接點處的保護基（例如羥基保護基，諸如硝基苯氧基羰基或四氫哌喃；或胺保護基，諸如三級丁氧基羰基）。在一些實施例中，L¹ 或L² 可不存在。 ^In Scheme ¹ , each of L1 and L2 is independently ^a moiety or derivative of L, or L1 can be H, or ^L2 can be L. The portion or derivative of L at L1 may include the remainder of L or ^a hydrogen atom at the point of attachment of ^G1 (eg, where L includes ^an oxygen or nitrogen atom such as attached to the parent structure, A1 ^- L1 may for the corresponding hydroxyl, amine or -C(O)NH ₂ ). The portion or derivative of L at L may contain ^a protecting group at the point of attachment of G (eg ^a hydroxy protecting group such as nitrophenoxycarbonyl or tetrahydropyran; or an amine protecting group such as tertiary butoxy carbonyl). In some embodiments, L ¹ or L ² may not be present.

在流程1中，L¹¹ 為適合於藉由與化合物103 反應將L² 附加至式X（c）之母體結構的L² 之衍生物。L¹¹ 可為適合的偶合搭配物或脫離基（例如

酸（boronic acid）、

酸酯，諸如4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基、假鹵化物或鹵化物，諸如氯、溴或碘）。舉例而言，式X（c）之化合物可與化合物103 在親核置換條件（例如親核芳族取代條件）下或在諸如鈀偶合條件或銅偶合條件之偶合條件下反應。在一些實施例中，L¹¹ 為氫。In Scheme ¹ , ^L11 is a derivative of L2 suitable for appending L2 to the parent structure of ^formula X(c) by reaction with compound 103 . L ¹¹ can be a suitable coupling partner or leaving group (eg

acid (boronic acid),

acid esters, such as 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl, pseudohalides or halides such as chlorine, bromine or iodine). For example, compounds of formula X(c) can be reacted with compound 103 under nucleophilic displacement conditions (eg, nucleophilic aromatic substitution conditions) or under coupling conditions such as palladium coupling conditions or copper coupling conditions. In some embodiments, L ¹¹ is hydrogen.

在流程1中，G¹ 為G或G之衍生物。G之衍生物可包含一或多個適用於附加T¹ 、T² 、T³ 、T⁴ 、T⁵ 及/或T⁶ 之部分（「T¹ -T⁶ 」），及/或G之衍生物可包含氮或氧保護基（例如THP）。因此，G之衍生物可包含胺（例如環胺，其中G包含哌啶基、哌

基或吡咯啶基）或經保護之胺（例如包含三級丁氧基羰基保護基）。G¹ 至G之轉化可包含在T¹ -T⁶ 之羰基或磺醯基部分處之置換反應以形成碳酸酯、胺基甲酸酯、尿素或磺醯胺（例如，其中G¹ 包含胺，可將G¹ 之胺添加至對應於T¹ -T⁶ 之胺磺醯氯或醯氯中）。G¹ 至G之轉化可替代地在T¹ -T⁶ 之一部分處包含親核置換反應（例如，Sn1或Sn2型反應）。舉例而言，在T¹ -T⁶ 包含α-羰基之情況下，反應可藉由假鹵化物（例如，磺酸酯，諸如(3-氰基雙環[1.1.1]戊基-1-基)甲基4-甲基苯磺酸酯）或鹵化物（例如溴，諸如2-溴乙酸三級丁酯）之Sn2置換來進行。In Scheme 1, G ¹ is G or a derivative of G. Derivatives of G may include one or more moieties suitable for appending T ¹ , T ² , T ³ , T ⁴ , T ⁵ and/or T ⁶ (“T ¹ -T ⁶ ”), and/or derivatives of G Compounds may contain nitrogen or oxygen protecting groups (eg THP). Thus, derivatives of G may include amines (eg, cyclic amines, where G includes piperidinyl, piperidine

or pyrrolidinyl) or a protected amine (e.g. containing a tertiary butoxycarbonyl protecting group). The transformation of G ¹ to G can comprise a displacement reaction at the carbonyl or sulfonyl moiety of T ¹ -T ⁶ to form a carbonate, carbamate, urea or sulfonamide (eg, wherein G ¹ comprises an amine, The amine of G ¹ can be added to the sulfasulfonyl chloride or acyl chloride corresponding to T ¹ -T ⁶ ). The conversion of ^G1 to G may alternatively comprise a nucleophilic displacement reaction (eg, Sn1 or Sn2 type reaction) at a portion of T1 ^{- T6} . For example, in the case where T ¹ -T ⁶ contain an α-carbonyl group, the reaction can be mediated by a pseudohalide (eg, a sulfonate, such as (3-cyanobicyclo[1.1.1]pentyl-1-yl) ) methyl 4-methylbenzenesulfonate) or Sn displacement of a halide such as bromine such as tert-butyl 2-bromoacetate.

在流程1中，R²¹ 為H，或R² 之經保護之衍生物，或適合的偶合搭配物（例如假鹵化物或鹵化物，諸如氯、溴或碘），或R²¹ 為R² 。In Scheme ¹ , ^R21 is H, or a protected derivative of R2, or a suitable coupling partner (eg, a pseudohalide or halide such as chlorine, bromine or iodine ⁾ , or ^R21 is R2.

在流程1中，R³¹ 為R³ 。共軛加成條件 In Scheme 1, R ³¹ is R ³ . Conjugate Addition Conditions

在適當情況下，例如，在將化合物101 (OH-A¹ -H)添加至式X（a）之化合物的情況下，可進行共軛加成反應。共軛加成反應在親核加成條件下（例如在鹼（諸如三乙胺、N,N -二異丙基-N -乙胺或碳酸鹽，例如碳酸鉀）存在下），在適合的溶劑（例如極性非質子溶劑、四氫呋喃、DMF等）中，視情況在惰性氛圍下進行。反應通常在約20至100℃之溫度下進行，持續約10分鐘至約7天。當反應基本上完成時，藉由習知手段分離產物。在一些實施例中，化合物101 為(R)-吡咯啶-3-醇或(3S ,4S )-4-氟吡咯啶-3-醇或其鹽。親核芳族取代條件 Conjugate addition reactions can be carried out where appropriate, eg, where compound 101 (OH-Ai ^- H) is added to a compound of formula X(a). The conjugate addition reaction is carried out under nucleophilic addition conditions (for example, in the presence of a base such as triethylamine, N,N -diisopropyl- N -ethylamine, or a carbonate, such as potassium carbonate), under a suitable In a solvent (such as polar aprotic solvent, tetrahydrofuran, DMF, etc.), it is carried out under an inert atmosphere as appropriate. The reaction is generally carried out at a temperature of about 20 to 100°C for about 10 minutes to about 7 days. When the reaction is substantially complete, the product is isolated by conventional means. In some embodiments, compound 101 is (R)-pyrrolidin-3-ol or (3S, 4S ) -4-fluoropyrrolidin-3-ol or a salt thereof. Nucleophilic Aromatic Substitution Conditions

適當時，例如在將化合物102 （L¹ -E¹¹ ）添加至式X（b）之化合物中時，可進行親核芳族取代反應。親核芳族取代反應在親核加成條件下（例如在鹼（諸如氫化鈉或碳酸銫）存在下），在適合的溶劑（例如極性非質子溶劑、1,4-二

烷、四氫呋喃、DMF等）中，視情況在惰性氛圍下進行。反應通常在約20至120℃之溫度下進行，持續約10分鐘至約7天。條件可包含離散去質子化步驟（例如其中鹼為氫化鈉）。當反應基本上完成時，藉由習知手段分離產物。在一些實施例中，化合物102 為2-氟吡啶、3-氟吡啶或4-氟吡啶（例如4-溴-5-氯-2-氟-吡啶）。鈀偶合條件 Where appropriate, a nucleophilic aromatic substitution reaction can be carried out, for example when compound 102 (L ¹ -E ¹¹ ) is added to a compound of formula X(b). Nucleophilic aromatic substitution reactions are carried out under nucleophilic addition conditions (eg in the presence of a base such as sodium hydride or cesium carbonate) in a suitable solvent (eg polar aprotic solvents, 1,4-dicarbonate)

alkane, tetrahydrofuran, DMF, etc.), as the case may be, in an inert atmosphere. The reaction is generally carried out at a temperature of about 20 to 120°C for about 10 minutes to about 7 days. Conditions may include discrete deprotonation steps (eg, where the base is sodium hydride). When the reaction is substantially complete, the product is isolated by conventional means. In some embodiments, compound 102 is 2-fluoropyridine, 3-fluoropyridine, or 4-fluoropyridine (eg, 4-bromo-5-chloro-2-fluoro-pyridine). Palladium Coupling Conditions

適當時，例如式X（a）、式X（b）、式X（c）或式X（d）之化合物、化合物102 、化合物103 或化合物104 ，其中Z¹ 、Z² 、E¹¹ 、L¹ 、L¹¹ 或G¹ 中之任一者包含適合的偶合搭配物，例如假鹵化物或鹵化物（例如氯）、或鋅試劑（例如氰化鋅），在經標準金屬催化之交叉偶合條件下（例如使用鈀催化劑）在適合的溶劑（例如甲苯、N,N -二甲基乙醯胺、二

烷、乙腈、水等）中，視情況在惰性氛圍下反應。在弱鹼（例如吡啶、碳酸鉀、碳酸鈉、碳酸氫鈉或三級丁醇鈉）存在下，在惰性溶劑（例如水性1,4-二

烷或水性N,N-二甲基甲醯胺）中進行偶合反應。反應通常在金屬催化劑存在下進行，例如參(二苯亞甲基丙酮)二鈀(0)、二氯雙(三苯基膦)鈀(II)或二氯1,1'-雙(二苯基膦基)二茂鐵鈀(II)、ruphos鈀環GEN 4，視情況在適當配位體（例如1,1'-雙(二苯基膦基)二茂鐵）之情況下，視情況在微波照射下，在約60至160℃之溫度下持續約10分鐘至約24小時。可密封反應。當反應基本上完成時，藉由習知手段分離產物。銅偶合條件 As appropriate, for example compounds of formula X(a), formula X(b), formula X(c) or formula X(d), compound 102 , compound 103 or compound 104 , wherein Z ¹ , Z ² , E ¹¹ , L ^1. Either L ¹¹ or G ¹ contains a suitable coupling partner, such as a pseudohalide or halide (eg, chlorine), or a zinc reagent (eg, zinc cyanide), under standard metal-catalyzed cross-coupling conditions in a suitable solvent (e.g. toluene, N,N -dimethylacetamide, dimethy

alkane, acetonitrile, water, etc.), and react in an inert atmosphere as appropriate. in the presence of a weak base such as pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium tert-butoxide in an inert solvent such as aqueous 1,4-dicarbonate

alkane or aqueous N,N-dimethylformamide) for the coupling reaction. The reaction is usually carried out in the presence of a metal catalyst such as bis(dibenzylideneacetone)dipalladium(0), dichlorobis(triphenylphosphine)palladium(II) or dichloro1,1'-bis(diphenylene) phosphino)ferrocene palladium(II), ruphos palladium ring GEN 4, as the case may be with the appropriate ligand (eg 1,1'-bis(diphenylphosphino)ferrocene), as the case may be Under microwave irradiation, at a temperature of about 60 to 160°C for about 10 minutes to about 24 hours. Sealable reactions. When the reaction is substantially complete, the product is isolated by conventional means. Copper Coupling Conditions

適當時，例如其中E¹ 或Z² 包括適合的偶合搭配物之式X（b）化合物，例如使鹵化物（例如氯、溴或碘）在銅催化之交叉偶合條件下在適合的溶劑中，視情況在惰性氛圍下反應以形成式X（c）或X（d）。偶合反應在惰性溶劑（例如甲苯或DMF）中，在弱鹼（例如碳酸銫）存在下，視情況在密封容器中進行。該反應通常在銅催化劑（例如碘化銅（I）（碘化亞銅））存在下，視情況在適當配位體（例如，3,4,7,8-四甲基-1,10-啡啉）下，在約60至150℃之溫度下進行，持續約10分鐘至約24小時。當反應基本上完成時，藉由習知手段分離產物。親核芳族取代條件 Where appropriate, for example ^a compound of ^formula X(b) wherein E or Z includes a suitable coupling partner, such as a halide (eg chlorine, bromine or iodine) in a suitable solvent under copper catalyzed cross-coupling conditions, The reaction is optionally carried out under an inert atmosphere to form formula X(c) or X(d). The coupling reaction is carried out in an inert solvent such as toluene or DMF in the presence of a weak base such as cesium carbonate, optionally in a sealed vessel. The reaction is typically carried out in the presence of a copper catalyst such as copper(I) iodide (cuprous iodide), optionally in the presence of an appropriate ligand such as 3,4,7,8-tetramethyl-1,10- phenanthrene) at a temperature of about 60 to 150° C. for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is isolated by conventional means. Nucleophilic Aromatic Substitution Conditions

適當時，例如在式X（d）之化合物轉化成式（I）之化合物的情況下，可進行親核置換反應。親核置換反應在親核加成條件下（例如在鹼（諸如氫化鈉、三級丁醇鈉或碳酸銫）存在下），在適合的溶劑（例如極性非質子溶劑、1,4-二

烷、四氫呋喃、DMF等）中，視情況在惰性氛圍下進行。反應通常在約20至160℃之溫度下進行，持續約10分鐘至約7天。條件可包含離散去質子化步驟（例如其中鹼為氫化鈉)，其可在-78℃至0℃下進行。當反應基本上完成時，藉由習知手段分離產物。在一些實施例中，對應於T¹ -T⁶ 之親電子劑為初始假鹵化物（例如，苯磺醯基）或鹵化物（例如，溴）。哌喃去保護條件 Where appropriate, a nucleophilic displacement reaction may be carried out, for example in the case of conversion of a compound of formula X(d) to a compound of formula (I). Nucleophilic displacement reactions are carried out under nucleophilic addition conditions (eg, in the presence of a base such as sodium hydride, sodium tertiary butoxide, or cesium carbonate) in a suitable solvent (eg, polar aprotic solvents, 1,4-dicarbonate).

alkane, tetrahydrofuran, DMF, etc.), as the case may be, in an inert atmosphere. The reaction is generally carried out at a temperature of about 20 to 160°C for about 10 minutes to about 7 days. Conditions can include discrete deprotonation steps (eg, where the base is sodium hydride), which can be performed at -78°C to 0°C. When the reaction is substantially complete, the product is isolated by conventional means. In some embodiments, the electrophiles corresponding to T ¹ -T ⁶ are initial pseudohalides (eg, benzenesulfonyl) or halides (eg, bromine). Piperan deprotection conditions

適當時，例如在式X（c）或X（d）之化合物包含哌喃保護基的情況下，例如在P¹ 或R¹⁵ 處，化合物可在經標準酸催化之去除保護條件（例如使用路易斯酸或質子酸）下，在適合的溶劑（例如1,4-二

烷、二氯甲烷、乙酸乙酯、乙腈、水、甲醇、乙醇等）中，視情況在惰性氛圍下反應形成R¹⁵ 或R¹ 。反應通常在酸催化劑（例如HCl或三氟乙酸）存在下，在約0至100℃之溫度下進行，持續約10分鐘至約24小時。當反應基本上完成時，藉由習知手段分離產物。在一些實施例中，用於哌喃去保護之起始物質可不經純化即自前述步驟進行。Where appropriate, for example where the compound of formula X(c) or X(d) contains ^a piperane protecting group, for example at P1 or ^R15 , the compound can be deprotected under standard acid catalyzed deprotection conditions (for example using Lewis acid or protic acid) in a suitable solvent such as 1,4-di

alkane, dichloromethane, ethyl acetate, acetonitrile, water, methanol, ethanol, etc.), as appropriate, under an inert atmosphere to form R ¹⁵ or R ¹ . The reaction is typically carried out in the presence of an acid catalyst such as HCl or trifluoroacetic acid at a temperature of about 0 to 100°C for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is isolated by conventional means. In some embodiments, the starting material for the deprotection of the pyran can be carried out from the preceding steps without purification.

熟習此項技術者將瞭解，對於一個特定實施例，式X（a）、X（b）或X（c）之化合物中之任一者可自商業供應商獲得。式X（a）、X（b）或X（c）之化合物之替代性合成可如本文所描述或如熟習此項技術者已知。Those skilled in the art will appreciate that, for a particular embodiment, any of the compounds of formula X(a), X(b) or X(c) are available from commercial suppliers. Alternative syntheses of compounds of formula X(a), X(b) or X(c) can be as described herein or as known to those skilled in the art.

中間物1

Intermediate 1

步驟 1 ：製備 4,5- 二氯 -2-( 四氫 -2H - 哌喃 -2- 基 ) 嗒

-3(2H )- 酮 2 ：4,5-二氯嗒

-3(2H )-酮（1 ，30 g，182 mmol）及對甲苯磺酸（1.6 g，9.1 mmol）合併於250 mL燒瓶中且添加四氫呋喃（100 mL）。隨後經由注射器添加3,4-二氫-2H -哌喃（18.4 g，218 mmol）且將反應物加熱至回流後持續15小時。LCMS分析指示轉化成產物及剩餘起始物質。將反應物濃縮至50 g矽膠上且藉由正相急驟管柱層析（120 g管柱，0-100%乙酸乙酯/己烷）純化，得到4,5-二氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（2 ）。MS (ESI)[M+H⁺ -THP]⁺ =248.9。 Step 1 : Preparation of 4,5 - dichloro -2-( tetrahydro - 2H -pyran -2- yl ) pyridine

-3( 2H ) -keto 2 : 4,5-dichlorota

-3( 2H )-one ( 1 , 30 g, 182 mmol) and p-toluenesulfonic acid (1.6 g, 9.1 mmol) were combined in a 250 mL flask and tetrahydrofuran (100 mL) was added. 3,4-Dihydro- 2H -pyran (18.4 g, 218 mmol) was then added via syringe and the reaction heated to reflux for 15 hours later. LCMS analysis indicated conversion to product and remaining starting material. The reaction was concentrated onto 50 g silica gel and purified by normal phase flash column chromatography (120 g column, 0-100% ethyl acetate/hexane) to give 4,5-dichloro-2-(tetrakis). Hydrogen- 2H -pyran-2-yl)da

-3( 2H )-one ( 2 ). MS(ESI)[M+H ⁺ -THP] ⁺ =248.9.

步驟 2 ：製備 4- 氯 -5-((R )-3- 羥基吡咯啶 -1- 基 )-2-( 四氫 -2H - 哌喃 -2- 基 ) 嗒

-3(2H )- 酮 3 ：向250 mL圓底燒瓶中添加4,5-二氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（2 ，9.35 g，37.5 mmol）及(R )-吡咯啶-3-醇鹽酸鹽（5.6 g，45.0 mmol）。隨後添加碳酸鉀（15.6 g，113 mmol）及N,N -二甲基甲醯胺（100 mL）且在室溫下攪拌反應物15小時。LCMS分析指示轉化成所需產物。將反應物濃縮至40 g矽膠上且藉由正相急驟管柱層析（120 g管柱，0-100%乙酸乙酯/己烷）純化，得到4-氯-5-((R )-3-羥基吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

基-3(2H )-酮（3 ）。MS (ESI)[M+H⁺ ]⁺ =300.2。 Step 2 : Preparation of 4- chloro- 5-(( R )-3 -hydroxypyrrolidin- 1 -yl )-2-( tetrahydro - 2H -pyran -2- yl ) pyridine

-3( 2H ) -one 3 : To a 250 mL round-bottomed flask was added 4,5-dichloro-2-(tetrahydro- 2H -pyran-2-yl)pyridine

-3( 2H )-one ( 2 , 9.35 g, 37.5 mmol) and ( R )-pyrrolidin-3-ol hydrochloride (5.6 g, 45.0 mmol). Potassium carbonate (15.6 g, 113 mmol) and N,N -dimethylformamide (100 mL) were then added and the reaction was stirred at room temperature for 15 hours. LCMS analysis indicated conversion to the desired product. The reaction was concentrated onto 40 g silica gel and purified by normal phase flash column chromatography (120 g column, 0-100% ethyl acetate/hexane) to give 4-chloro-5-(( R )- 3-Hydroxypyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

base-3( 2H )-one ( 3 ). MS (ESI)[M+H ⁺ ] ⁺ =300.2.

中間物2

Intermediate 2

步驟1：製備5-((R )-3-((4-溴吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基）嗒

-3(2H )-酮 4：向250 mL圓底燒瓶中添加4-氯-5-((R )-3-羥基吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（3，4.0 g，13.3 mmol）、4-溴-2-氟-吡啶（2.8 g，16.0 mmol）、碳酸銫（8.7 g，26.7 mmol）及N,N -二甲基甲醯胺（50 mL）。在油浴中在80℃下攪拌反應物18小時。LCMS分析指示轉化成所需產物。將反應物濃縮至20 g矽膠上，且通過正相急驟管柱層析純化（120 g矽膠管柱，0至100%乙酸乙酯/己烷），得到5-((R )-3-((4-溴吡啶)-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（4）。MS (ESI)[M+H⁺ ]⁺ =455.1。Step 1: Preparation of 5-(( R )-3-((4-bromopyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro-2-(tetrahydro- 2H -pyran -2-base) click

-3( 2H )-one 4: To a 250 mL round bottom flask was added 4-chloro-5-(( R )-3-hydroxypyrrolidin-1-yl)-2-(tetrahydro- 2H -piperidine pyran-2-yl)da

-3( 2H )-one (3, 4.0 g, 13.3 mmol), 4-bromo-2-fluoro-pyridine (2.8 g, 16.0 mmol), cesium carbonate (8.7 g, 26.7 mmol) and N,N -bismuth Methylformamide (50 mL). The reaction was stirred at 80°C for 18 hours in an oil bath. LCMS analysis indicated conversion to the desired product. The reaction was concentrated onto 20 g silica gel and purified by normal phase flash column chromatography (120 g silica gel column, 0 to 100% ethyl acetate/hexane) to give 5-(( R )-3-( (4-Bromopyridin)-2-yl)oxy)pyrrolidin-1-yl)-4-chloro-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one (4). MS(ESI)[M+H ⁺ ] ⁺ =455.1.

實例 1

Example 1

步驟1：製備4-氯-5-((3S ,4S )-3-氟-4-羥基吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮 5：向250 mL圓底燒瓶中添加4,5-二氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（2，7.2 g，28.9 mmol）及(3S ,4S )-4-氟吡咯啶-3-醇鹽酸鹽（4.5 g，31.8mmol）。隨後添加碳酸鉀（16.0 g，116 mmol）及N,N -二甲基甲醯胺（100 mL）且在室溫下攪拌反應物15小時。LCMS分析指示轉化成所需產物。將反應物濃縮至40 g矽膠上且藉由正相急驟管柱層析（120 g管柱，0-100%乙酸乙酯/己烷）純化，得到4-氯-5-((3S,4S)-3-氟-4-羥基吡咯啶-1-基)-2-(四氫-2H-哌喃-2-基)嗒

-3(2H)-酮（5）。MS (ESI)[M+H⁺ -THP]⁺ =234.1。Step 1: Preparation of 4-chloro-5-( (3S,4S ) -3-fluoro-4-hydroxypyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl) despair

-3( 2H )-one 5: To a 250 mL round bottom flask was added 4,5-dichloro-2-(tetrahydro- 2H -pyran-2-yl)sodium

-3( 2H )-one (2, 7.2 g, 28.9 mmol) and (3S, 4S ) -4-fluoropyrrolidin-3-ol hydrochloride (4.5 g, 31.8 mmol). Potassium carbonate (16.0 g, 116 mmol) and N,N -dimethylformamide (100 mL) were then added and the reaction was stirred at room temperature for 15 hours. LCMS analysis indicated conversion to the desired product. The reaction was concentrated onto 40 g silica gel and purified by normal phase flash column chromatography (120 g column, 0-100% ethyl acetate/hexanes) to give 4-chloro-5-((3S,4S )-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-2-yl)da

-3(2H)-one (5). MS(ESI)[M+H ⁺ -THP] ⁺ =234.1.

步驟2：製備5-[(3S ,4S )-3-[(4-溴-2-吡啶基)氧基]-4-氟-吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮 6：向250 mL圓底燒瓶中添加4-氯-5-[(3S ,4S )-3-氟-4-羥基-吡咯啶-1-基-2-四氫哌喃-2-基-嗒

-3-酮（5，4.0 g，12.6 mmol）、4-溴-2-氟-吡啶（2.7 g，15.1 mmol）、碳酸銫（8.2 g，25.2 mmol）及N,N -二甲基甲醯胺（50 ml）。在油浴中在80℃下攪拌反應物18小時。LCMS分析指示轉化成所需產物。將反應物濃縮至20 g矽膠上，且通過正相急驟管柱層析純化（120 g矽膠管柱，0至100%乙酸乙酯/己烷），得到5-[(3S ,4S )-3-[(4-溴-2-吡啶基)氧基]-4-氟-吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（6）。MS (ESI)[M+H⁺ ]⁺ =473.0。Step 2: Preparation of 5-[( 3S,4S ) -3-[(4-bromo-2-pyridyl)oxy]-4-fluoro-pyrrolidin-1-yl]-4-chloro-2- Tetrahydropyran-2-yl-da

-3-one 6: To a 250 mL round bottom flask was added 4-chloro-5-[ (3S,4S ) -3-fluoro-4-hydroxy-pyrrolidin-1-yl-2-tetrahydropyran -2-base-tat

-3-one (5, 4.0 g, 12.6 mmol), 4-bromo-2-fluoro-pyridine (2.7 g, 15.1 mmol), cesium carbonate (8.2 g, 25.2 mmol) and N,N -dimethylformamide Amine (50 ml). The reaction was stirred at 80°C for 18 hours in an oil bath. LCMS analysis indicated conversion to the desired product. The reaction was concentrated onto 20 g silica gel and purified by normal phase flash column chromatography (120 g silica gel column, 0 to 100% ethyl acetate/hexane) to give 5-[( 3S,4S ) -3-[(4-Bromo-2-pyridyl)oxy]-4-fluoro-pyrrolidin-1-yl]-4-chloro-2-tetrahydropyran-2-yl-da

-3-keto (6). MS (ESI)[M+H ⁺ ] ⁺ =473.0.

步驟3：製備4-氯-5-((3S ,4S )-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H )-酮 7：在250 mL圓底燒瓶中，向5-((3S,4S)-3-((4-溴吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-4-氯-2-(四氫-2H-哌喃-2-基)嗒

-3(2H)-酮（6，4.6 g，9.8 mmol）、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)異

唑（3.3 g，14.7 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）於1,4-二

烷（90 ml）中之丙酮加合物（772 mg，0.98 mmol）中添加1 M碳酸鉀水溶液（29 ml）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。在溫度下攪拌反應物兩小時。將反應物冷卻至室溫且濃縮於20 g矽膠上。藉由正相急驟管柱層析（120 g矽石管柱，0至100%乙酸乙酯/己烷）純化反應物，得到中間產物。隨後將此物質溶解於20 mL二氯甲烷且添加鹽酸（4 M於1,4-二

烷中，20 mL，80 mmol），且在室溫下攪拌反應物30分鐘。濃縮反應物，得到4-氯-5-((3S ,4S )-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H )-酮（7）。MS (ESI)[M+H⁺ ]⁺ =406.2。Step 3: Preparation of 4-chloro-5-(( 3S,4S ) -3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3( 2H )-one 7: In a 250 mL round bottom flask, add 5-((3S,4S)-3-((4-bromopyridin-2-yl)oxy)-4-fluoropyrrolidine -1-yl)-4-chloro-2-(tetrahydro-2H-pyran-2-yl)da

-3(2H)-one (6, 4.6 g, 9.8 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro cyclopentan-2-yl)iso

azole (3.3 g, 14.7 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) in 1,4-bis(II)

To the acetone adduct (772 mg, 0.98 mmol) in alkane (90 ml) was added 1 M aqueous potassium carbonate (29 ml). The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was stirred at temperature for two hours. The reaction was cooled to room temperature and concentrated on 20 g of silica gel. The reaction was purified by normal phase flash column chromatography (120 g silica column, 0 to 100% ethyl acetate/hexanes) to give the intermediate product. This material was then dissolved in 20 mL of dichloromethane and hydrochloric acid (4 M in 1,4-dichloromethane was added)

hexane, 20 mL, 80 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated to give 4-chloro-5-(( 3S,4S ) -3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3( 2H )-one (7). MS (ESI)[M+H ⁺ ] ⁺ =406.2.

步驟4：製備4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮（P-0179）：將4-氯-5-((3S ,4S )-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H )-酮（7，4.0 g，9.9 mmol）溶解於N,N -二甲基甲醯胺（40 mL）且添加碳酸鉀（2.7 g，19.7 mmol）。隨後添加2-(2-溴乙氧基)四氫-2H -哌喃（2.7 g，12.8 mmol）且在60℃下攪拌反應物15小時。LCMS指示轉化成4-氯-5-((3S ,4S )-3-((4-(3,5-二甲基

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-((四氫-2H -哌喃-2-基)氧基)乙基)嗒

-3(2H )-酮。濾出固體碳酸鉀且將粗反應物與鹽酸（4 M於1,4-二

烷中，20 mL，80 mmol）混合。在室溫下攪拌反應物兩小時。用20 mL甲醇淬滅反應，且濃縮至60 g矽膠上。此物質隨後藉由反相急驟層析（415 g C18管柱；0-45% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN、0.1% HCO₂ H）純化。此純化仍提供不純產物。隨後藉由正相層析（40 g矽膠管柱，0-100%乙酸乙酯/己烷）純化物質。此純化提供4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)吡啶)-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮（P-0179）。MS (ESI)[M+H⁺ ]⁺ =450.1。Step 4: Preparation of 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one ( P -0179): 4-chloro-5-((3S, 4S )-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3( 2H )-one (7, 4.0 g, 9.9 mmol) was dissolved in N,N -dimethylformamide (40 mL) and potassium carbonate (2.7 g, 19.7 mmol) was added. 2-(2-Bromoethoxy)tetrahydro- 2H -pyran (2.7 g, 12.8 mmol) was then added and the reaction was stirred at 60 °C for 15 h. LCMS indicated conversion to 4-chloro-5-(( 3S,4S ) -3-((4-(3,5-dimethyl

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-((tetrahydro- 2H -pyran-2-yl)oxy) ethyl)ta

-3( 2H )-one. Solid potassium carbonate was filtered off and the crude reaction was mixed with hydrochloric acid (4 M in 1,4-dicarbonate)

alkane, 20 mL, 80 mmol) and mixed. The reaction was stirred at room temperature for two hours. The reaction was quenched with 20 mL of methanol and concentrated onto 60 g of silica gel. This material was subsequently purified by reverse phase flash chromatography (415 g C18 column; 0-45% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2H )purification. This purification still provided an impure product. The material was then purified by normal phase chromatography (40 g silica gel column, 0-100% ethyl acetate/hexane). This purification provides 4-chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin)-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one (P-0179). MS (ESI)[M+H ⁺ ] ⁺ =450.1.

實例 2

Example 2

步驟 1 ：製備 4,5- 二溴 -2-( 四氫 -2H- 哌喃 -2- 基 ) 嗒

-3(2H)- 酮 9 ：在螺帽式反應容器中裝入4,5-二溴-1H-嗒

-6-酮（8 ，1.00 g，3.95 mmol）、3,4-二氫-2H-哌喃（1.00 g，11.9 mmol）、DCE（25 ml）及PTSA單水合物（0.195 g，1.03 mmol）。密封反應容器且使其在油浴中在70℃下攪拌16小時。隨後冷卻反應物且用乙酸乙酯及水萃取，過濾兩次以除去顆粒。分離有機層，經硫酸鎂乾燥，且過濾。藉由旋轉蒸發除去揮發物，且藉由矽膠急驟管柱層析（40 g矽膠管柱，0至60%乙酸乙酯/己烷）純化所得殘餘物。此純化提供4,5-二溴-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（9 ）。MS (ESI)[M+H⁺ ]⁺ =338.8。 Step 1 : Preparation of 4,5 -dibromo -2-( tetrahydro -2H -pyran -2- yl ) pyridine

-3(2H) -ketone 9 : Charge 4,5-dibromo-1H-pyridine in a screw-cap reaction vessel

-6-one ( 8 , 1.00 g, 3.95 mmol), 3,4-dihydro-2H-pyran (1.00 g, 11.9 mmol), DCE (25 ml) and PTSA monohydrate (0.195 g, 1.03 mmol) . The reaction vessel was sealed and allowed to stir in an oil bath at 70°C for 16 hours. The reaction was then cooled and extracted with ethyl acetate and water, filtered twice to remove particles. The organic layer was separated, dried over magnesium sulfate, and filtered. Volatiles were removed by rotary evaporation and the resulting residue was purified by silica gel flash column chromatography (40 g silica gel column, 0 to 60% ethyl acetate/hexane). This purification provides 4,5-dibromo-2-(tetrahydro- 2H -pyran-2-yl)pyridine

-3( 2H )-one ( 9 ). MS (ESI)[M+H ⁺ ] ⁺ =338.8.

步驟 2 ：製備 4- 溴 -5-((R )-3- 羥基吡咯啶 -1- 基 )-2-( 四氫 -2H - 哌喃 -2- 基 ) 嗒

-3(2H )- 酮 10 ：向裝有4,5-二溴-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（9 ，0.43 g，1.27 mmol）之圓底燒瓶中添加(3R )-吡咯啶-3-醇鹽酸鹽（0.189 g，1.53 mmol），隨後添加N,N -二甲基甲醯胺（10 ml）。向此溶液中添加三乙胺（0.27 ml，1.91 mmol）。使反應物在室溫下攪拌四天。在減壓下除去所有揮發物，且用乙酸乙酯及水萃取所得殘餘物。再萃取水層四次，直至藉由TLC水層不再含有產物。使經合併之有機層經硫酸鎂乾燥且過濾。藉由旋轉蒸發除去揮發物且藉由矽膠急驟管柱層析（24 g矽膠管柱，0至6%甲醇/二氯甲烷）純化所得殘餘物。此純化提供4-溴-5-((R )-3-羥基吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（10 ）。MS (ESI)[M+H⁺ ]⁺ =344.0。 Step 2 : Preparation of 4- bromo - 5-(( R )-3 -hydroxypyrrolidin- 1 -yl )-2-( tetrahydro - 2H -pyran -2- yl ) pyridine

-3( 2H ) -one 10 : to which 4,5-dibromo-2-(tetrahydro- 2H -pyran-2-yl) was added

To a round bottom flask of -3( 2H )-one ( 9 , 0.43 g, 1.27 mmol) was added ( 3R )-pyrrolidin-3-ol hydrochloride (0.189 g, 1.53 mmol) followed by N,N - Dimethylformamide (10 ml). To this solution was added triethylamine (0.27 ml, 1.91 mmol). The reaction was allowed to stir at room temperature for four days. All volatiles were removed under reduced pressure and the resulting residue was extracted with ethyl acetate and water. The aqueous layer was extracted four more times until the aqueous layer contained no more product by TLC. The combined organic layers were dried over magnesium sulfate and filtered. Volatiles were removed by rotary evaporation and the resulting residue was purified by flash column chromatography on silica gel (24 g silica gel column, 0 to 6% methanol/dichloromethane). This purification provides 4-bromo-5-(( R )-3-hydroxypyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one ( 10 ). MS (ESI)[M+H ⁺ ] ⁺ =344.0.

步驟3：製備4-溴-5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮 11：向1,4-二

烷（10 ml）中之4-溴-5-((R )-3-羥基吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（10，195 mg，0.567 mmol）中添加氫化鈉（於礦物油中之60%，25 mg，0.62 mmol）。在停止氣體逸出之後，添加4-(2-氟-4-吡啶基)-3,5-二甲基-異

唑（122 mg，0.635 mmol），且使反應物在氬氣氛圍下在油浴中在60℃下攪拌六小時，隨後在80℃下再攪拌17小時。在減壓下除去反應揮發物且將所得殘餘物乾燥裝載至來自THF/MeOH之二氧化矽上且藉由矽膠急驟管柱層析（24 g管柱，50%至100%乙酸乙酯/己烷）純化。此純化提供4-溴-5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（11）。MS (ESI)[M+H⁺ ]⁺ =515.5。Step 3: Preparation of 4-bromo-5-[( 3R )-3-[[4-(3,5-dimethyliso

oxazol-4-yl)-2-pyridinyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto 11: to 1,4-di

4-Bromo-5-(( R )-3-hydroxypyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)pyridine in alkane (10 ml)

To -3( 2H )-one (10, 195 mg, 0.567 mmol) was added sodium hydride (60% in mineral oil, 25 mg, 0.62 mmol). After gas evolution ceased, 4-(2-fluoro-4-pyridyl)-3,5-dimethyl-iso was added

azole (122 mg, 0.635 mmol), and the reaction was stirred in an oil bath under argon atmosphere at 60 °C for six hours, followed by an additional 17 hours at 80 °C. Reaction volatiles were removed under reduced pressure and the resulting residue was dry loaded onto silica from THF/MeOH and purified by silica gel flash column chromatography (24 g column, 50% to 100% ethyl acetate/hexane alkane) purification. This purification provides 4-bromo-5-[( 3R )-3-[[4-(3,5-dimethyliso

oxazol-4-yl)-2-pyridinyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto (11). MS (ESI)[M+H ⁺ ] ⁺ =515.5.

步驟4：5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-4-(三氟甲基)嗒

-3-酮 12：向N,N -二甲基甲醯胺（2 ml）中之2,2-二氟-2-氟磺醯基乙酸甲酯（79 mg，0.41 mmol）及4-溴-5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（11，101 mg，0.196 mmol）添加碘化銅（I）（122 mg，0.383 mmol）。將混合物在100℃下加熱15小時。使反應物冷卻且用THF稀釋。使THF不溶物質沈降且將可溶溶離份乾燥裝載於矽膠上且藉由矽膠急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/己烷）純化。此純化提供5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-4-(三氟甲基)嗒

-3-酮（12）。MS (ESI)[M+H⁺ ]⁺ =506.1。Step 4: 5-[( 3R )-3-[[4-(3,5-Dimethyliso

oxazol-4-yl)-2-pyridyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl)da

-3-keto 12: methyl 2,2-difluoro-2-fluorosulfonamidoacetate (79 mg, 0.41 mmol) and 4-bromoacetate in N,N -dimethylformamide (2 ml) -5-[(3 R )-3-[[4-(3,5-dimethyliso

oxazol-4-yl)-2-pyridinyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-one (11, 101 mg, 0.196 mmol) was added copper(I) iodide (122 mg, 0.383 mmol). The mixture was heated at 100°C for 15 hours. The reaction was cooled and diluted with THF. The THF insoluble material was allowed to settle and the soluble fraction was dry loaded on silica and purified by silica flash column chromatography (12 g silica column, 0 to 100% ethyl acetate/hexane). This purification provides 5-[( 3R )-3-[[4-(3,5-dimethyliso

oxazol-4-yl)-2-pyridyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl)da

-3-keto (12). MS (ESI)[M+H ⁺ ] ⁺ =506.1.

步驟5：製備(R )-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-(三氟甲基)嗒

-3(2H )-酮（P-0053）：向裝有5-[(3R )-3-[[4-(3,5-二甲基異

唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-4-(三氟甲基)嗒

-3-酮（12，6.0 mg，0.01 mmol）的圓底燒瓶中添加二氯甲烷（5 ml），隨後添加三氟乙酸（0.5 ml，6.53 mmol）。使溶液在環境溫度下攪拌2小時。在減壓下除去揮發物，得到(R )-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-(三氟甲基)嗒

-3(2H )-酮（P-0053）。MS (ESI)[M+H⁺ ]⁺ =422.0。Step 5: Preparation of ( R )-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine

-3( 2H )-ketone (P-0053): added to the compound containing 5-[( 3R )-3-[[4-(3,5-dimethyliso

oxazol-4-yl)-2-pyridyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-4-(trifluoromethyl)da

-3-one (12, 6.0 mg, 0.01 mmol) was added to a round bottom flask with dichloromethane (5 ml) followed by trifluoroacetic acid (0.5 ml, 6.53 mmol). The solution was allowed to stir at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to give ( R )-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine

-3( 2H )-one (P-0053). MS (ESI)[M+H ⁺ ] ⁺ =422.0.

實例 3

Example 3

步驟1：製備5-((R )-3-((4-溴-5-氯吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮 13：在小瓶中，向N,N -二甲基甲醯胺（5 ml）中之4-氯-5-[(3R )-3-羥基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（3，0.30 g，1.0 mmol）及碳酸銫（1.27 g，4.0 mmol）中添加4-溴-5-氯-2-氟-吡啶（0.27 g，1.28 mmol）。在室溫下攪拌反應混合物3天。過濾反應物以除去碳酸銫。在真空下除去揮發物。將此物質直接裝載於矽膠上且藉由正相急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/己烷）純化。此純化提供5-((R )-3-((4-溴-5-氯吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（13）。MS (ESI)[M+H⁺ ]⁺ =488.8。Step 1: Preparation of 5-(( R )-3-((4-bromo-5-chloropyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro-2-(tetrahydro-2 H -pyran-2-yl)da

-3( 2H )-one 13: 4-chloro-5-[( 3R )-3-hydroxypyrrolidine-1 in N,N -dimethylformamide (5 ml) in a vial -yl]-2-tetrahydropyran-2-yl-da

-3-One (3, 0.30 g, 1.0 mmol) and cesium carbonate (1.27 g, 4.0 mmol) were added 4-bromo-5-chloro-2-fluoro-pyridine (0.27 g, 1.28 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction was filtered to remove cesium carbonate. The volatiles were removed under vacuum. This material was loaded directly onto silica gel and purified by normal phase flash column chromatography (12 g silica gel column, 0 to 100% ethyl acetate/hexane). This purification provides 5-(( R )-3-((4-bromo-5-chloropyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one (13). MS (ESI)[M+H ⁺ ] ⁺ =488.8.

步驟2：製備4-氯-5-((R )-3-((5-氯-4-(4-(吡咯啶-1-基磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮 14：在10 mL微波小瓶中，向1,4-二

烷（2 ml）中之5-[(3R )-3-[(4-溴-5-氯-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（13，50 mg，0.1 mmol）、(4-吡咯啶-1-基磺醯基苯基)

酸（40 mg，0.16 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（15 mg，0.019 mmol）中添加1 M碳酸鉀水溶液（1 ml，1 mmol）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。在溫度下攪拌反應物5分鐘。向經冷卻之反應混合物中添加水及乙酸乙酯。分離有機層且用水及鹽水洗滌，之後經硫酸鎂乾燥。在真空下在5 g矽膠上除去揮發物。隨後藉由正相急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/二氯甲烷）純化粗物質。此純化提供4-氯-5-[(3R )-3-[[5-氯-4-(4-吡咯啶-1-基磺醯基苯基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（14）。MS (ESI)[M+H⁺ ]⁺ =620.0。Step 2: Preparation of 4-chloro-5-(( R )-3-((5-chloro-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy )pyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one 14: In a 10 mL microwave vial, add 1,4-di

5-[( 3R )-3-[(4-bromo-5-chloro-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro-2-tetrakis in alkane (2 ml) Hydropyran-2-yl-da

-3-one (13, 50 mg, 0.1 mmol), (4-pyrrolidin-1-ylsulfonylphenyl)

To the acid (40 mg, 0.16 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (15 mg, 0.019 mmol) was added 1 M aqueous potassium carbonate (1 ml, 1 mmol). The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was stirred at temperature for 5 minutes. To the cooled reaction mixture was added water and ethyl acetate. The organic layer was separated and washed with water and brine before drying over magnesium sulfate. Remove volatiles on 5 g of silica gel under vacuum. The crude material was then purified by normal phase flash column chromatography (12 g silica gel column, 0 to 100% ethyl acetate/dichloromethane). This purification provides 4-chloro-5-[( 3R )-3-[[5-chloro-4-(4-pyrrolidin-1-ylsulfonylphenyl)-2-pyridyl]oxy]pyrrole Perid-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto (14). MS(ESI)[M+H ⁺ ] ⁺ =620.0.

步驟3：製備(R )-4-氯-5-(3-((5-氯-4-(4-(吡咯啶-1-基磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0250）：在40 mL小瓶中，向1,4-二

烷（2 ml）中之4-氯-5-[(3R )-3-[[5-氯-4-(4-吡咯啶-1-基磺醯基苯基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（14，40 mg，0.064 mmol）中添加鹽酸（4 M於1,4-二

烷中，9 mL，36 mmol）。在室溫下攪拌反應混合物2小時。在真空下除去揮發物。藉由製備型HPLC（C18管柱；0-60% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）直接純化粗物質。此純化提供(R )-4-氯-5-(3-((5-氯-4-(4-(吡咯啶-1-基磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0250）。MS (ESI)[M+H⁺ ]⁺ =535.9。Step 3: Preparation of ( R )-4-chloro-5-(3-((5-chloro-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy )pyrrolidin-1-yl)pyridine

-3( 2H )-one (P-0250): in a 40 mL vial, add 1,4-di

4-Chloro-5-[( 3R )-3-[[5-chloro-4-(4-pyrrolidin-1-ylsulfonylphenyl)-2-pyridyl] in alkane (2 ml) Oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-one (14, 40 mg, 0.064 mmol) was added hydrochloric acid (4 M in 1,4-di

alkane, 9 mL, 36 mmol). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under vacuum. The crude material was directly purified by preparative HPLC (C18 column; 0-60% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2H ). This purification afforded ( R )-4-chloro-5-(3-((5-chloro-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3( 2H )-one (P-0250). MS (ESI)[M+H ⁺ ] ⁺ =535.9.

實施例 4

Example 4

步驟 1 ：製備 5-[(3R)-3-(3- 溴苯氧基 ) 吡咯啶 -1- 基 ]-4- 氯 -2- 四氫哌喃 -2- 基 - 嗒

-3- 酮 15 ：向20 mL微波小瓶中添加4-氯-5-[(3R)-3-羥基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（3，0.30 g，1.0 mmol）、1-溴-3-碘苯（0.19 ml，1.5 mmol）、碘化亞銅（10 mg，0.05 mmol）、3,4,7,8-四甲基-1,10-啡啉（24 mg，0.1 mmol）、碳酸銫（489 mg，1.5 mmol）及甲苯（5 ml）。將小瓶密封，脫氣，且在120℃下在氮氣氛圍下攪拌18小時。將反應混合物傾入鹽水中且用乙酸乙酯萃取。將有機層經無水硫酸鈉乾燥、過濾且蒸發至矽膠上。藉由正相急驟管柱層析（24 g矽膠管柱，0至100%乙酸乙酯/己烷）純化反應物，得到5-[(3R )-3-(3-溴苯氧基)吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（15 ）。MS (ESI)[M+H⁺ ]⁺ =453.9。 Step 1 : Preparation of 5-[(3R)-3-(3- bromophenoxy ) pyrrolidin- 1 -yl ]-4 -chloro -2- tetrahydropyran- 2- yl - pyridin

-3 -keto 15 : To a 20 mL microwave vial was added 4-chloro-5-[(3R)-3-hydroxypyrrolidin-1-yl]-2-tetrahydropyran-2-yl-pyridine

-3-keto (3, 0.30 g, 1.0 mmol), 1-bromo-3-iodobenzene (0.19 ml, 1.5 mmol), cuprous iodide (10 mg, 0.05 mmol), 3,4,7,8- Tetramethyl-1,10-phenanthroline (24 mg, 0.1 mmol), cesium carbonate (489 mg, 1.5 mmol) and toluene (5 ml). The vial was sealed, degassed, and stirred at 120°C under nitrogen atmosphere for 18 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated onto silica gel. The reaction was purified by normal phase flash column chromatography (24 g silica gel column, 0 to 100% ethyl acetate/hexanes) to give 5-[( 3R )-3-(3-bromophenoxy) Pyrrolidin-1-yl]-4-chloro-2-tetrahydropyran-2-yl-da

-3-keto ( 15 ). MS (ESI)[M+H ⁺ ] ⁺ =453.9.

步驟2：製備(R )-4-氯-5-(3-(3-(1,3,5-三甲基-1H -吡唑-4-基)苯氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0200）：向5 mL微波小瓶中添加5-[(3R )-3-(3-溴苯氧基)吡咯啶-1-基]-4-氯-2-四氫哌喃- 2-基-嗒

-3-酮（15，0.15 g，0.33 mmol）、1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)吡唑（0.12 g，0.50 mmol）、二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.026 g，0.033 mmol）、碳酸鉀水溶液（1 M，0.66 ml，0.66 mmol）及1,4-二

烷（2 ml）。將小瓶密封且在100℃下照射30分鐘。將反應物過濾，蒸發至矽膠上，且藉由反相急驟管柱層析（30 g C18管柱；0-70% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化得到經THP保護之中間物。將經保護之中間物溶解於二氯甲烷（2 mL）中且用鹽酸（4 M於1,4-二

烷中，0.80 ml，3.2 mmol)處理。在室溫下攪拌反應物2小時且蒸發至乾，得到(R )-4-氯-5-(3-(3-(1,3,5-三甲基-1H -吡唑-4-基)苯氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0200）。MS (ESI)[M+H⁺ ]⁺ =400.0。Step 2: Preparation of ( R )-4-chloro-5-(3-(3-(1,3,5-trimethyl- 1H -pyrazol-4-yl)phenoxy)pyrrolidine-1- base)

-3( 2H )-one (P-0200): To a 5 mL microwave vial was added 5-[( 3R )-3-(3-bromophenoxy)pyrrolidin-1-yl]-4-chloro -2-Tetrahydropyran-2-yl-da

-3-keto (15, 0.15 g, 0.33 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)pyrazole (0.12 g, 0.50 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.026 g, 0.033 mmol), Aqueous potassium carbonate (1 M, 0.66 ml, 0.66 mmol) and 1,4-di

alkane (2 ml). The vial was sealed and irradiated at 100°C for 30 minutes. The reaction was filtered, evaporated onto silica gel, and purified by reverse phase flash column chromatography (30 g C18 column; 0-70% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % _CH3CN , 0.1% _HCO2H ). This purification yielded the THP protected intermediate. The protected intermediate was dissolved in dichloromethane (2 mL) and diluted with hydrochloric acid (4 M in 1,4-dichloromethane)

alkane, 0.80 ml, 3.2 mmol). The reaction was stirred at room temperature for 2 hours and evaporated to dryness to give ( R )-4-chloro-5-(3-(3-(1,3,5-trimethyl- 1H -pyrazole-4- yl)phenoxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0200). MS (ESI)[M+H ⁺ ] ⁺ =400.0.

實例 5

Example 5

步驟 1 ：製備 4-(6- 氯嗒

-4- 基 )-3,5- 二甲基異

唑 17 ：向5 mL微波小瓶中添加5-溴-3-氯-嗒

（16，0.1 g，0.52 mmol）、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)異

唑（0.14 g，0.62 mmol）、二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.04 g，0.05 mmol）、1 M碳酸鉀水溶液（1.03 ml）及1,4-二

烷（2 ml）。將小瓶密封、脫氣，且在100℃下照射30分鐘。將反應物蒸發至矽膠上且藉由反相急驟管柱層析（30 g C18管柱；0-70% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到4-(6-氯嗒

-4-基)-3,5--二甲基異

唑（17 ）。MS (ESI)[M+H⁺ ]⁺ =210.0。 Step 1 : Preparation of 4-(6- Chloropyridine

-4 -yl )-3,5 -dimethyliso

Azole 17 : Add 5-bromo-3-chloro-pyridine to a 5 mL microwave vial

(16, 0.1 g, 0.52 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)iso

oxazole (0.14 g, 0.62 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.04 g, 0.05 mmol), 1 M aqueous potassium carbonate ( 1.03 ml) and 1,4-di

alkane (2 ml). The vial was sealed, degassed, and irradiated at 100°C for 30 minutes. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-70% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3 CN, 0.1% HCO ₂ H) to give 4-(6-chloropyridine)

-4-yl)-3,5--dimethyliso

azoles ( 17 ). MS (ESI)[M+H ⁺ ] ⁺ =210.0.

步驟2：製備(R )-4-氯-5-(3-((5-(3,5-二甲基異

唑-4-基)嗒

-3-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0160）：向20 mL閃爍小瓶中添加4-氯-5-[(3R )-3-羥基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（3，0.10 g，0.33 mmol）、4-(6-氯嗒

-4-基)-3,5-二甲基-異

唑（17，0.070 g，0.33 mmol）及N,N-二甲基甲醯胺（5 mL）。添加氫化鈉（60%於礦物油中，16 mg，0.67 mmol）且在室溫下攪拌反應物2小時。將反應物蒸發至矽膠上且藉由反相急驟管柱層析（30 g C18管柱；0-70% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，以提供經THP保護之中間物。將經THP保護之中間物溶解於二氯甲烷（5 mL）中，用鹽酸（4 M於1,4-二

烷中，0.83 mL，3.3 mmol）處理，且在室溫下攪拌2小時。將反應物蒸發至矽膠上且藉由反相急驟管柱層析（30 g C18管柱；0-50%B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到(R )-4-氯-5-(3-((5-(3,5-二甲基異

唑-4-基)嗒

-3-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮（P-0160）。MS (ESI)[M+H⁺ ]⁺ =389.0。Step 2: Preparation of ( R )-4-chloro-5-(3-((5-(3,5-dimethyliso

oxazol-4-yl)da

-3-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0160): To a 20 mL scintillation vial was added 4-chloro-5-[( 3R )-3-hydroxypyrrolidin-1-yl]-2-tetrahydropyran -2-base-tat

-3-keto (3, 0.10 g, 0.33 mmol), 4-(6-Chloropyridine

-4-yl)-3,5-dimethyl-iso

azole (17, 0.070 g, 0.33 mmol) and N,N-dimethylformamide (5 mL). Sodium hydride (60% in mineral oil, 16 mg, 0.67 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-70% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3 CN, 0.1% _HCO2H ) to provide the THP protected intermediate. The THP-protected intermediate was dissolved in dichloromethane (5 mL) and treated with hydrochloric acid (4 M in 1,4-dichloromethane).

hexane, 0.83 mL, 3.3 mmol) and stirred at room temperature for 2 hours. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3 CN, 0.1% _HCO2H ) to give ( R )-4-chloro-5-(3-((5-(3,5-dimethyliso

oxazol-4-yl)da

-3-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one (P-0160). MS (ESI)[M+H ⁺ ] ⁺ =389.0.

實例 6

Example 6

步驟1：製備4-氯-5-((R )-3-((6-氯嘧啶-4-基)氧基)吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮 18：在250 mL圓底燒瓶中，合併4-氯-5-[(3R )-3-羥基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（3，3.0 g，10.0 mmol）、4,6-二氯嘧啶（2.98 g，20.0 mmol）及N,N -二甲基甲醯胺（100 mL）。使反應混合物冷卻至0℃且逐份添加氫化鈉（60%於礦物油中，0.48 g，20.0 mmol）。攪拌反應物，同時在2小時內緩慢升溫至室溫。將反應物傾入冷飽和氯化銨中且用乙酸乙酯萃取。有機層用鹽水洗滌，過濾且蒸發至矽膠上。藉由正相急驟管柱層析（40 g矽膠管柱，0至100%乙酸乙酯/己烷）分離產物，得到4-氯-5-[(3R )-3-(6-氯嘧啶-4-基)氧基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（18）。MS (ESI)[M+H⁺ ]⁺ =412.0。Step 1: Preparation of 4-chloro-5-(( R )-3-((6-chloropyrimidin-4-yl)oxy)pyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran -2-base) click

-3( 2H )-one 18: In a 250 mL round bottom flask, combine 4-chloro-5-[( 3R )-3-hydroxypyrrolidin-1-yl]-2-tetrahydropyran-2 -base-tat

-3-one (3, 3.0 g, 10.0 mmol), 4,6-dichloropyrimidine (2.98 g, 20.0 mmol) and N,N -dimethylformamide (100 mL). The reaction mixture was cooled to 0 °C and sodium hydride (60% in mineral oil, 0.48 g, 20.0 mmol) was added portionwise. The reaction was stirred while slowly warming to room temperature over 2 hours. The reaction was poured into cold saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, filtered and evaporated onto silica gel. The product was isolated by normal phase flash column chromatography (40 g silica gel column, 0 to 100% ethyl acetate/hexanes) to give 4-chloro-5-[( 3R )-3-(6-chloropyrimidine) -4-yl)oxypyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto (18). MS (ESI)[M+H ⁺ ] ⁺ =412.0.

步驟2：製備(R )-4-氯-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮 19：在5 mL微波小瓶中，合併4-氯-5-[(3R )-3-(6-氯嘧啶-4-基)氧基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（18，0.10 g，0.24 mmol）、[3-(甲氧基甲基)-5-甲基-異

唑-4-基]

酸（0.050 g，0.29 mmol）、二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.020 g，0.02 mmol）、1 M碳酸鉀水溶液（0.49 mL，0.49 mmol）及1,4-二

烷（3 mL）。將小瓶置於氮氣氛圍下且在100℃下照射40分鐘。將反應物蒸發至矽膠上，且藉由反相急驟管柱層析（30 g C18管柱；0-70% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）分離經THP保護之中間物。將中間物溶解於二氯甲烷（5 mL）中，用鹽酸（4 M於1,4-二

烷中，0.61 mL，2.4 mmol）處理，且在室溫下攪拌2小時。將反應混合物蒸發至乾，溶解於N,N -二甲基甲醯胺（2 mL）中，且藉由反相管柱層析法（30 g C18管柱； 0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到(R )-4-氯-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基))嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（19）。MS (ESI)[M+H⁺ ]⁺ =419.0。Step 2: Preparation of ( R )-4-chloro-5-(3-((6-(3-(methoxymethyl)-5-methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one 19: In a 5 mL microwave vial, combine 4-chloro-5-[( 3R )-3-(6-chloropyrimidin-4-yl)oxypyrrolidin-1-yl ]-2-Tetrahydropyran-2-yl-da

-3-one (18, 0.10 g, 0.24 mmol), [3-(methoxymethyl)-5-methyl-iso

azol-4-yl]

acid (0.050 g, 0.29 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.020 g, 0.02 mmol), 1 M aqueous potassium carbonate ( 0.49 mL, 0.49 mmol) and 1,4-di

alkane (3 mL). The vial was placed under a nitrogen atmosphere and irradiated at 100°C for 40 minutes. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-70% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% CH _3CN , 0.1% _HCO2H ) isolated the THP protected intermediate. The intermediate was dissolved in dichloromethane (5 mL) and diluted with hydrochloric acid (4 M in 1,4-dichloromethane)

hexane, 0.61 mL, 2.4 mmol) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, dissolved in N,N -dimethylformamide (2 mL), and subjected to reverse phase column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2H ) Purification to give ( R )-4-chloro-5-(3-((6-(3-( Methoxymethyl)-5-methyliso

oxazol-4-yl))pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (19). MS (ESI)[M+H ⁺ ] ⁺ =419.0.

步驟3：製備(R )-4-氯-2-(2-羥乙基)-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0126）：在20 mL閃爍小瓶中，合併(R )-4-氯-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（19，0.040 g，0.080 mmol）、N,N-二甲基甲醯胺（3 mL）、碳酸鉀（0.020 g，0.17 mmol）及2-(2-溴乙氧基)四氫-2H -哌喃（0.030 mL，0.17 mmol）。在70℃下攪拌反應物3小時。將反應物冷卻至室溫且添加鹽酸（4 M於1,4-二

烷中，0.42 mL，1.68 mmol），且攪拌反應物2小時。將反應混合物蒸發至矽膠上，且藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）分離產物，得到(R )-4-氯-2-(2-羥乙基)-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0126）。MS (ESI)[M+H⁺ ]⁺ =463.0。Step 3: Preparation of ( R )-4-Chloro-2-(2-hydroxyethyl)-5-(3-((6-(3-(methoxymethyl)-5-methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0126): In a 20 mL scintillation vial, combine ( R )-4-chloro-5-(3-((6-(3-(methoxymethyl)- 5-methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (19, 0.040 g, 0.080 mmol), N,N-dimethylformamide (3 mL), potassium carbonate (0.020 g, 0.17 mmol) and 2-(2-bromoethyl) oxy)tetrahydro- 2H -pyran (0.030 mL, 0.17 mmol). The reaction was stirred at 70°C for 3 hours. The reaction was cooled to room temperature and hydrochloric acid (4 M in 1,4-dihydrochloric acid was added)

alkane, 0.42 mL, 1.68 mmol), and the reaction was stirred for 2 hours. The reaction mixture was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% CH _3CN , 0.1% _HCO2H ) isolated the product to give ( R )-4-chloro-2-(2-hydroxyethyl)-5-(3-((6-(3-(methoxymethyl)) -5-Methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0126). MS(ESI)[M+H ⁺ ] ⁺ =463.0.

實例 7

Example 7

步驟 1 ： (R)-4- 氯 -5-(3-((4-( 哌

-1- 基 ) 吡啶 -2- 基 ) 氧基 ) 吡咯啶 -1- 基 ) 嗒

-3(2H)- 酮 20 ：向乾燥的5 mL微波小瓶中添加5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4 ，0.30 g，0.66 mmol）、丁基哌

-1-甲酸三級丁酯（0.25 g，1.32 mmol）、（2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2-胺乙基)苯基)]氯化鈀（II）（0.050 g，0.07 mmol）、碳酸銫（0.32 g，0.99 mmol）及1,4-二

烷（5 mL）。將小瓶密封且在油浴中加熱至80℃持續12小時。將反應物蒸發至矽膠上且藉由反相急驟管柱層析（50 g C18管柱；0-70% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到雙保護之中間物。將此物質溶解於二氯甲烷（5 mL）中且用鹽酸（4 M於1,4-二

烷中，0.82 ml，3.3 mmol）處理。在室溫下攪拌2小時之後，將反應物蒸發至乾，得到(R )-4-氯-5-(3-((4-哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（20 ）。MS (ESI)[M+H⁺ ]⁺ =377.0。 Step 1 : (R)-4 -Chloro -5-(3-((4-( piperidine

-1 -yl ) pyridin -2- yl ) oxy ) pyrrolidin- 1 -yl ) da

-3(2H) -one 20 : To a dry 5 mL microwave vial was added 5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]- 4-Chloro-2-tetrahydropyran-2-yl-da

-3-one ( 4 , 0.30 g, 0.66 mmol), butylpiperidine

- Tertiary butyl 1-carboxylate (0.25 g, 1.32 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2- (2-Aminoethyl)phenyl)]palladium(II) chloride (0.050 g, 0.07 mmol), cesium carbonate (0.32 g, 0.99 mmol) and 1,4-dicarbonate

alkane (5 mL). The vial was sealed and heated to 80°C in an oil bath for 12 hours. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (50 g C18 column; 0-70% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3 CN, 0.1% _HCO2H ) to give the doubly protected intermediate. This material was dissolved in dichloromethane (5 mL) and diluted with hydrochloric acid (4 M in 1,4-dichloromethane)

alkane, 0.82 ml, 3.3 mmol). After stirring at room temperature for 2 hours, the reaction was evaporated to dryness to give ( R )-4-chloro-5-(3-((4-piperidine

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one ( 20 ). MS (ESI)[M+H ⁺ ] ⁺ =377.0.

步驟2：製備(R )-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基哌

-1-磺醯胺（P-0231）：向20 mL閃爍小瓶中添加(R )-4-氯-5-(3-((4-哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（20，0.050 g，0.11 mmol）、吡啶（0.88 ml，10.9 mmol）及N -環丙基氨磺醯氯（0.020 g，0.13 mmol）。在室溫下攪拌反應物2小時。將反應物蒸發至矽膠上且藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到(R )-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N -環丙基哌

-1-磺醯胺（P-0231）。MS (ESI)[M+H⁺ ]⁺ =496.0。Step 2: Preparation of ( R )-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylpiperin

-1-Sulfonamide (P-0231): To a 20 mL scintillation vial was added ( R )-4-chloro-5-(3-((4-piperidine

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (20, 0.050 g, 0.11 mmol), pyridine (0.88 ml, 10.9 mmol) and N -cyclopropylsulfamoyl chloride (0.020 g, 0.13 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was evaporated onto silica gel and purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3 CN, 0.1% HCO ₂ H) to give ( R )-4-(2-((1-(5-chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl) -N -cyclopropylpiper

-1-Sulfonamide (P-0231). MS (ESI)[M+H ⁺ ] ⁺ =496.0.

實例 8

Example 8

步驟1：製備5-((R )-3-((4-(4-胺基-2-氟苯基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮 21：在20 mL微波小瓶中，向1,4二

烷（10 mL）中之5-[(3R )-3-[(4-溴-2-四氫哌喃-2-基-嗒

-3-酮（4，0.50 g，1.1 mmol）、3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯胺（0.46 g，1.9 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.15 g，0.19 mmol）中添加1 M碳酸鉀水溶液（5 mL）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。反應在不到5分鐘內完成。將反應物濃縮至10 g矽膠上，且藉由反相急驟管柱層析（50 g C18管柱；0-60% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，得到5-((R )-3-((4-(4-胺基-2-氟苯基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（21）。MS (ESI)[M+H⁺ ]⁺ =486.0。Step 1: Preparation of 5-(( R )-3-((4-(4-amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro- 2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one 21: In a 20 mL microwave vial, add 1,4 two

5-[(3 R )-3-[(4-bromo-2-tetrahydropyran-2-yl-pyridine in alkane (10 mL)

-3-keto (4, 0.50 g, 1.1 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (0.46 g, 1.9 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.15 g, 0.19 mmol) were added 1 M aqueous potassium carbonate ( 5 mL). The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was complete in less than 5 minutes. The reaction was concentrated onto 10 g silica gel and purified by reverse phase flash column chromatography (50 g C18 column; 0-60% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % CH ₃ CN, 0.1% HCO ₂ H) purification to give 5-(( R )-3-((4-(4-amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidine -1-yl)-4-chloro-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one (21). MS (ESI)[M+H ⁺ ] ⁺ =486.0.

步驟2：製備(R )-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)苯甲醯胺（P-0216）：將5-((R )-3-((4-(4-胺基-2-氟苯基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯-2-（四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（21，40 mg，0.082 mmol）溶解於二氯甲烷（2 mL）且添加三乙胺（25 mg，0.25 mmol）。在室溫下劇烈攪拌的同時，一次性添加苯甲醯氯（14 mg，0.099 mmol），且在室溫下攪拌反應物2小時。向粗反應物中添加鹽酸（4 M於1,4-二

烷中，2 mL，8 mmol）且在室溫下攪拌混合物30分鐘。隨後將反應物濃縮至10 g矽膠上，且藉由反相層析法（50 g C18管柱；0-60% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供(R )-N -(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)苯甲醯胺（P-0216）。MS (ESI)[M+H⁺ ]⁺ =506.0。Step 2: Preparation of ( R )-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)benzamide (P-0216): 5-(( R )-3-(( 4-(4-Amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro-2-(tetrahydro- 2H -pyran-2-yl )despair

-3( 2H )-one (21, 40 mg, 0.082 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (25 mg, 0.25 mmol) was added. While stirring vigorously at room temperature, benzyl chloride (14 mg, 0.099 mmol) was added in one portion, and the reaction was stirred at room temperature for 2 hours. To the crude reaction was added hydrochloric acid (4 M in 1,4-di

hexane, 2 mL, 8 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction was then concentrated onto 10 g silica gel and analyzed by reverse phase chromatography (50 g C18 column; 0-60% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2H ) purification. This purification provides ( R )-N-(4-(2-((1-(5 - chloro-6-oxo-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)benzamide (P-0216). MS (ESI)[M+H ⁺ ] ⁺ =506.0.

實例 9

Example 9

步驟1：製備5,5'-((3R ,3'R )-(吡啶-3,5-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯-2-(四氫-2H-哌喃-2-基)嗒

-3(2H )-酮) 22：在小瓶中，向N,N -二甲基甲醯胺（5 mL）中之4-氯-5-[(3R )-3-羥基吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（3，500 mg，1.67 mmol）、碘化亞銅（20.0 mg，0.11 mmol）及3,4,7,8-四甲基-1,10-啡啉（0.04 ml，0.17 mmol）中添加3-溴-5-碘-吡啶（500 ml，1.76 mmol）及碳酸銫（850 mg，2.61 mmol）。將反應混合物加熱至100℃後維持16小時。偵測到三種產物，包括少量所需產物。過濾粗反應物且濃縮至矽膠上。隨後藉由正相急驟管柱層析（24 g矽膠管柱，0至100%乙酸乙酯/二氯甲烷梯度）純化此物質。該純化提供5,5'-((3R ,3'R )-(吡啶-3,5-二基雙(氧基)雙(吡咯啶-3,1-二基))雙(4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮)（22）。MS (ESI)[M+H⁺ ]⁺ =674.1。Step 1: Preparation of 5,5'-(( 3R , 3'R )-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4 -Chloro-2-(tetrahydro-2H-pyran-2-yl)da

-3( 2H )-one) 22: In a vial, to N,N -dimethylformamide (5 mL) 4-chloro-5-[( 3R )-3-hydroxypyrrolidine- 1-yl]-2-tetrahydropyran-2-yl-da

-3-one (3,500 mg, 1.67 mmol), cuprous iodide (20.0 mg, 0.11 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.04 ml, 0.17 mmol) ) was added 3-bromo-5-iodo-pyridine (500 ml, 1.76 mmol) and cesium carbonate (850 mg, 2.61 mmol). The reaction mixture was heated to 100°C for 16 hours. Three products were detected, including a small amount of the desired product. The crude reaction was filtered and concentrated onto silica gel. This material was subsequently purified by normal phase flash column chromatography (24 g silica gel column, 0 to 100% ethyl acetate/dichloromethane gradient). This purification provides 5,5'-(( 3R , 3'R )-(pyridine-3,5-diylbis(oxy)bis(pyrrolidine-3,1-diyl))bis(4-chloro -2-(Tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one) (22). MS (ESI)[M+H ⁺ ] ⁺ =674.1.

步驟2：製備5,5'- ((3R ,3'R )-(吡啶-3,5-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯嗒

-3(2H )-酮)（P-0165）：在40 mL小瓶中，向1,4-二

烷（2 mL）中之5,5'-((3R ,3'R )-(吡啶-3,5-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮)（22，40 mg，0.060 mmol）中添加鹽酸（4 M於1,4-二

烷中，6 mL，24 mmol）。在室溫下攪拌反應混合物2小時。在減壓下除去揮發物且將該物質溶解於2 mL N,N-二甲基甲醯胺中。此物質隨後藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN、0.1% HCO₂ H）純化。此純化提供5,5'-((3R ,3'R )-(吡啶-3,5-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯嗒

-3(2H )-酮)（P-0165）。MS (ESI)[M+H⁺ ]⁺ =505.9。Step 2: Preparation of 5,5'-(( 3R , 3'R )-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4 - Chloro

-3( 2H )-one) (P-0165): in a 40 mL vial, add 1,4-di

5,5'-((3 R ,3' R )-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl)) in alkane (2 mL) Bis(4-chloro-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one) (22, 40 mg, 0.060 mmol) was added hydrochloric acid (4 M in 1,4-di

alkane, 6 mL, 24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the material was dissolved in 2 mL of N,N-dimethylformamide. This material was subsequently purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% HCO 2H ₎ Purification. This purification provides 5,5'-(( 3R , 3'R )-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4- Chloride

-3( 2H )-one) (P-0165). MS (ESI)[M+H ⁺ ] ⁺ =505.9.

實例 10

Example 10

步驟1：製備4-氯-5-((R )-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(四氫-2H -吡喃-2-基)嗒

-3(2H )-酮 23：在10 mL微波小瓶中，向1,4-二

烷（4 mL）中之5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，0.20 g，0.44 mmol）、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)異

唑（0.20 g，0.90 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.050 g，0.060 mmol）中添加1 M碳酸鉀水溶液（2 mL，2.0 mmol）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。反應在不到5分鐘內完成。將反應混合物傾入水中且用乙酸乙酯萃取。用水及鹽水洗滌有機層，隨後經硫酸鎂乾燥。將有機層濃縮至矽膠上且藉由正相急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/二氯甲烷梯度）純化。此純化提供4-氯-5-((R )-3-((4-(3,5-二甲基

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（23）。MS (ESI)[M+H⁺ ]⁺ =472.3。Step 1: Preparation of 4-chloro-5-(( R )-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one 23: In a 10 mL microwave vial, add 1,4-di

5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro-2-tetrahydropyran- in alkane (4 mL)- 2-base-tat

-3-one (4, 0.20 g, 0.44 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -base) iso

azole (0.20 g, 0.90 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.050 g, 0.060 mmol) was added with 1 M aqueous potassium carbonate (2 mL, 2.0 mmol). The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was completed in less than 5 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The organic layer was concentrated onto silica gel and purified by normal phase flash column chromatography (12 g silica gel column, 0 to 100% ethyl acetate/dichloromethane gradient). This purification provides 4-chloro-5-(( R )-3-((4-(3,5-dimethyl

oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

-3( 2H )-one (23). MS (ESI)[M+H ⁺ ] ⁺ =472.3.

步驟2：製備(R )-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-3-側氧基-2,3-二氫嗒

-4-腈（P-0065）：在小瓶中，向4-氯-5-((R )-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(四氫-2H -哌喃-2-基)嗒

-3(2H )-酮（23，156 mg，0.33 mmol）中添加N,N-二甲基乙醯胺（5 mL）。藉由用氬氣鼓泡使溶液脫氣。在室溫下在氬氣下，向此溶液中添加鋅粉（10 mg，0.15 mmol）、1,1'-雙(二苯基膦基)二茂鐵（16 mg，0.030 mmol）、參(二苯亞甲基丙酮)二鈀（0）（15 mg，0.030 mmol）及氰化鋅（50 mg，0.43 mmol）。在120℃下加熱混合物20小時。冷卻至室溫之後，將反應混合物傾入碳酸氫鈉水溶液（飽和）中且用乙酸乙酯萃取。用水及鹽水洗滌有機層，隨後經硫酸鎂乾燥。將此溶液濃縮至矽膠上且藉由正相急驟管柱層析（12 g矽膠管柱，0至80%乙酸乙酯/二氯甲烷梯度，隨後藉由0至10%甲醇/二氯甲烷梯度）純化。收集經粗THP保護之產物且將殘餘物溶解於1,4-二

烷（2 mL）中且添加鹽酸（4 M於1,4-二

烷中，8 mL，32 mmol）。在室溫下攪拌混合物2小時。濃縮反應物，且隨後溶解於2 mLN,N -二甲基甲醯胺中。此溶液藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化，以提供(R )-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-3-側氧基-2,3-二氫嗒

-4-腈（P-0065）。MS (ESI)[M+H⁺ ]⁺ =379.3。Step 2: Preparation of ( R )-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-3-oxy-2,3-dihydropyridine

-4-Nitrile (P-0065): In a vial, to 4-chloro-5-(( R )-3-((4-(3,5-dimethyliso

oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(tetrahydro- 2H -pyran-2-yl)da

To -3( 2H )-one (23, 156 mg, 0.33 mmol) was added N,N-dimethylacetamide (5 mL). The solution was degassed by bubbling with argon. To this solution were added zinc powder (10 mg, 0.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene (16 mg, 0.030 mmol), ginseng (16 mg, 0.030 mmol) at room temperature under argon. Dibenzylideneacetone) dipalladium(0) (15 mg, 0.030 mmol) and zinc cyanide (50 mg, 0.43 mmol). The mixture was heated at 120°C for 20 hours. After cooling to room temperature, the reaction mixture was poured into aqueous sodium bicarbonate solution (saturated) and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. This solution was concentrated onto silica gel and purified by normal phase flash column chromatography (12 g silica gel column, 0 to 80% ethyl acetate/dichloromethane gradient followed by 0 to 10% methanol/dichloromethane gradient )purification. The crude THP protected product was collected and the residue was dissolved in 1,4-di

alkane (2 mL) and hydrochloric acid (4 M in 1,4-di

alkane, 8 mL, 32 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and then dissolved in 2 mL of N,N -dimethylformamide. This solution was purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2 H) Purification to provide ( R )-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-3-oxy-2,3-dihydropyridine

-4-Nitrile (P-0065). MS (ESI)[M+H ⁺ ] ⁺ =379.3.

實例 11

Example 11

步驟1：製備4-氯-5-[(3R )-3-[[4-(3,5-二甲基-1H -吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮 24：在250 mL圓底燒瓶中，向1,4-二

烷（50 ml）中之5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，2.0 g，4.39 mmol）、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1H-吡唑（1.46 g，6.6 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.35 g，0.44 mmol）中添加1 M碳酸鉀水溶液（13 mL，13 mmol）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。在100℃下攪拌反應物4小時。將反應物濃縮至50 g矽膠上，且藉由反相急驟管柱層析（150 g C18管柱；0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供4-氯-5-[(3R )-3-[[4-(3,5-二甲基-1H -吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（24）。MS (ESI)[M+H⁺ ]⁺ =471.3。Step 1: Preparation of 4-chloro-5-[( 3R )-3-[[4-(3,5-dimethyl- 1H -pyrazol-4-yl)-2-pyridinyl]oxy] Pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto 24: In a 250 mL round bottom flask, add 1,4-di

5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro-2-tetrahydropyran- in alkane (50 ml)- 2-base-tat

-3-one (4, 2.0 g, 4.39 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -yl)-1H-pyrazole (1.46 g, 6.6 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.35 g, 0.44 mmol) 1 M aqueous potassium carbonate solution (13 mL, 13 mmol) was added. The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was stirred at 100°C for 4 hours. The reaction was concentrated onto 50 g silica gel and purified by reverse phase flash column chromatography (150 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % _CH3CN , 0.1% _HCO2H ). This purification provides 4-chloro-5-[( 3R )-3-[[4-(3,5-dimethyl- 1H -pyrazol-4-yl)-2-pyridyl]oxy]pyrrole Perid-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto (24). MS (ESI)[M+H ⁺ ] ⁺ =471.3.

步驟2：製備2-[4-[2-[(3R )-1-(5-氯-6-側氧基-1H-嗒

-4-基)吡咯啶-3-基]氧基-4-吡啶基]-3,5-二甲基-吡唑-1-基]乙酸25：將4-氯-5-[(3R )-3-[[4-(3,5-二甲基-1H -吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（24，250 mg，0.53 mmol）及2-溴乙酸三級丁酯（207 mg，1.1 mmol）溶解於N,N -二甲基甲醯胺（5mL）且添加氫化鈉（60%於礦物油中，42 mg，1.1 mmol）。在室溫下攪拌反應物15小時隔夜。將反應物濃縮至10 g矽膠上且藉由正相急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/己烷）純化。此純化得到中間物雙保護之產物。將此物質溶解於20 mL二氯甲烷中且添加鹽酸（4 M於1,4-二

烷中，5 mL，20 mmol）。在室溫下攪拌反應物30分鐘。將反應物濃縮，得到2-[4-[2-[(3R)-1-(5-氯-6-側氧基-1H-嗒

-4-基)吡咯啶-3-基]氧基-4-吡啶基]-3,5-二甲基-吡唑-1-基]乙酸（25）。MS (ESI)[M+H⁺ ]⁺ =445.2。Step 2: Preparation of 2-[4-[2-[( 3R )-1-(5-chloro-6-oxy-1H-pyridoxine

-4-yl)pyrrolidin-3-yl]oxy-4-pyridinyl]-3,5-dimethyl-pyrazol-1-yl]acetic acid 25: 4-chloro-5-[( 3R )-3-[[4-(3,5-Dimethyl- 1H -pyrazol-4-yl)-2-pyridyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran -2-base-tat

-3-keto (24, 250 mg, 0.53 mmol) and tert-butyl 2-bromoacetate (207 mg, 1.1 mmol) were dissolved in N,N -dimethylformamide (5 mL) and sodium hydride (60 mL) was added. % in mineral oil, 42 mg, 1.1 mmol). The reaction was stirred at room temperature for 15 hours overnight. The reaction was concentrated onto 10 g silica gel and purified by normal phase flash column chromatography (12 g silica gel column, 0 to 100% ethyl acetate/hexane). This purification gave the intermediate doubly protected product. This material was dissolved in 20 mL of dichloromethane and hydrochloric acid (4 M in 1,4-dichloromethane was added)

alkane, 5 mL, 20 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was concentrated to give 2-[4-[2-[(3R)-1-(5-chloro-6-oxo-1H-pyridoxine

-4-yl)pyrrolidin-3-yl]oxy-4-pyridyl]-3,5-dimethyl-pyrazol-1-yl]acetic acid (25). MS (ESI)[M+H ⁺ ] ⁺ =445.2.

步驟3：製備(R )-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)-N-環丙基乙醯胺 P-0042：將2-[4-[2-[(3R )-1-(5-氯-6-側氧基-1H-嗒

-4-基)吡咯啶-3-基]氧基-4-吡啶基]-3,5-二甲基-吡唑-1-基]乙酸（25，50 mg，0.112 mmol）溶解於N,N-二甲基甲醯胺（1 mL）且添加HBTU（55 mg，0.10 mmol）及環丙胺（26 mg，0.45 mmol）。在室溫下劇烈攪拌的同時，一次性添加三乙胺（45 mg，0.45 mmol）且攪拌反應物15小時隔夜。反應物隨後藉由反相急驟管柱層析（50 g C18管柱；0-50% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN、0.1% HCO₂ H）直接純化。此純化提供(R)-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)-N-環丙基乙醯胺（P-0042）。MS (ESI)[M+H⁺ ]⁺ =484.3。Step 3: Preparation of ( R )-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)-N-cyclopropylacetamide P -0042: 2-[4-[2-[(3 R )-1-(5-chloro-6-oxo-1H-pa

-4-yl)pyrrolidin-3-yl]oxy-4-pyridinyl]-3,5-dimethyl-pyrazol-1-yl]acetic acid (25,50 mg, 0.112 mmol) was dissolved in N, N-Dimethylformamide (1 mL) and HBTU (55 mg, 0.10 mmol) and cyclopropylamine (26 mg, 0.45 mmol) were added. While stirring vigorously at room temperature, triethylamine (45 mg, 0.45 mmol) was added in one portion and the reaction was stirred for 15 hours overnight. The reaction was then purified by reverse phase flash column chromatography (50 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% HCO 2H ₎ Direct purification. This purification provides (R)-2-(4-(2-((1-(5-chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-cyclopropylacetamide (P -0042). MS (ESI)[M+H ⁺ ] ⁺ =484.3.

實例 12

Example 12

步驟1：製備4-氯-5-[(3R )-3-[[4-(3,5-二甲基-1H -吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮 24：在250 mL圓底燒瓶中，向1,4-二

烷（50 ml）中之5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，2.0 g，4.39 mmol）、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1H-吡唑（1.46 g，6.6 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.35 g，0.44 mmol）中添加1 M碳酸鉀水溶液（13 mL，13 mmol）。緊接著在油浴中在100℃下加熱反應混合物，該油浴經預加熱至100℃。在100℃下攪拌反應物4小時。將反應物濃縮至50 g矽膠上，且藉由反相急驟管柱層析（150 g C18管柱；0-50% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供4-氯-5-[(3R)-3-[[4-(3,5-二甲基-1H-吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（24）。MS (ESI)[M+H⁺ ]⁺ =471.3。Step 1: Preparation of 4-chloro-5-[( 3R )-3-[[4-(3,5-dimethyl- 1H -pyrazol-4-yl)-2-pyridinyl]oxy] Pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-keto 24: In a 250 mL round bottom flask, add 1,4-di

5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro-2-tetrahydropyran- in alkane (50 ml)- 2-base-tat

-3-one (4, 2.0 g, 4.39 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -yl)-1H-pyrazole (1.46 g, 6.6 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.35 g, 0.44 mmol) 1 M aqueous potassium carbonate solution (13 mL, 13 mmol) was added. The reaction mixture was then heated at 100°C in an oil bath that was preheated to 100°C. The reaction was stirred at 100°C for 4 hours. The reaction was concentrated onto 50 g silica gel and purified by reverse phase flash column chromatography (150 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % _CH3CN , 0.1% _HCO2H ). This purification provides 4-chloro-5-[(3R)-3-[[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-pyridyl]oxy]pyrrolidine- 1-yl]-2-tetrahydropyran-2-yl-da

-3-keto (24). MS (ESI)[M+H ⁺ ] ⁺ =471.3.

步驟2：製備3-((4-(2-(((3R )-1-(5-氯-6-側氧基-1-(四氫-2H -哌喃-2-基)-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈 26：在小瓶中，向N,N-二甲基甲醯胺（2 mL）中之4-氯-5-[(3R )-3-[[4-(3,5-二甲基-1H -吡唑-4-基)-2-吡啶基]氧基]吡咯啶-1-基]-2-四氫哌喃-2-基-嗒

-3-酮（24，0.060 g，0.13 mmol）中添加氫化鈉（60%於礦物油中，0.010 g，0.34 mmol）。在室溫下攪拌反應物15分鐘。此時，添加(3-氰基雙環[1.1.1]戊烷-1-基)甲基4-甲基苯磺酸酯（0.060 g，0.22 mmol）且在室溫下攪拌反應物16小時。過濾反應物以除去不溶物質且濃縮於矽膠上。隨後藉由正相急驟管柱層析（12 g矽膠管柱，0至100%乙酸乙酯/二氯甲烷梯度）純化此物質。此純化提供3-((4-(2-(((3R )-1-(5-氯-6-側氧基-1-(四氫-2H -哌喃-2-基)-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（26）。MS (ESI)[M+H⁺ ]⁺ =576.3。Step 2: Preparation of 3-((4-(2-((( 3R )-1-(5-chloro-6-oxy-1-(tetrahydro- 2H -pyran-2-yl)- 1,6-Dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile 26: In a vial, add 4-chloro-5-[( 3R )-3-[[4-(3,5 to N,N-dimethylformamide (2 mL) -Dimethyl- 1H -pyrazol-4-yl)-2-pyridyl]oxy]pyrrolidin-1-yl]-2-tetrahydropyran-2-yl-da

-3-one (24, 0.060 g, 0.13 mmol) was added sodium hydride (60% in mineral oil, 0.010 g, 0.34 mmol). The reaction was stirred at room temperature for 15 minutes. At this time, (3-cyanobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate (0.060 g, 0.22 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was filtered to remove insoluble material and concentrated on silica gel. This material was subsequently purified by normal phase flash column chromatography (12 g silica gel column, 0 to 100% ethyl acetate/dichloromethane gradient). This purification afforded 3-((4-(2-((( 3R )-1-(5-chloro-6-oxy-1-(tetrahydro- 2H -pyran-2-yl)-1 ,6-Dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile (26). MS (ESI)[M+H ⁺ ] ⁺ =576.3.

步驟3：製備(R )-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈27：在40 mL小瓶中，向二氯甲烷（10 mL）中之3-((4-(2-(((3R )-1-(5-氯-6-側氧基-1-(四氫-2H -哌喃-2-基)-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（26，48 mg，0.080 mmol）中添加三氟乙酸（1mL）。在室溫下攪拌反應混合物2小時。在減壓下濃縮反應物且溶解於2 mL N,N-二甲基甲醯胺中。此溶液隨後藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN、0.1% HCO₂ H）純化。此純化提供(R )-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（27）。MS (ESI)[M+H⁺ ]⁺ =492.3。Step 3: Preparation of ( R )-3-((4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile 27: In a 40 mL vial, add 3-((4-(2-((( 3R )-1-(5-chloro-6-oxygen in dichloromethane (10 mL) Base-1-(tetrahydro- 2H -pyran-2-yl)-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane To the alkane-1-carbonitrile (26, 48 mg, 0.080 mmol) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and dissolved in 2 mL of N,N-dimethylformamide. This solution was then purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% HCO 2H ₎ Purification. This purification provides ( R )-3-((4-(2-((1-(5-chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile (27). MS (ESI)[M+H ⁺ ] ⁺ =492.3.

步驟4：製備(R )-3-((4-(2-((1-(5-氯-1-(2-羥乙基)-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（P-0036）：在小瓶中，向N,N-二甲基甲醯胺（2 mL）中之(R )-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（27，18 mg，0.040 mmol）中添加碳酸鉀（0.15 g，1.1 mmol）及2-(2-溴乙氧基)四氫哌喃（50 mg，0.24 mmol）。將反應混合物加熱至60℃持續16小時。過濾反應物以除去不溶物質且在減壓下濃縮。向此物質中添加二氯甲烷（8 mL）及三氟乙酸（1 mL）。在室溫下攪拌反應混合物2小時。在減壓下濃縮反應物且溶解於2 mL N,N-二甲基甲醯胺中。此溶液藉由反相急驟管柱層析（30 g C18管柱；0-50% B；A：99.9% H₂ O、0.1% HCO₂ H；B：99.9% CH₃ CN、0.1% HCO₂ H）純化。此純化提供(R )-3-((4-(2-((1-(5-氯-1-(2-羥乙基)-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H -吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈（P-0036）。MS (ESI)[M+H⁺ ]⁺ =536.3。Step 4: Preparation of ( R )-3-((4-(2-((1-(5-Chloro-1-(2-hydroxyethyl)-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile (P-0036): In a vial, add ( R )-3-(((4-(2-(((1-() to N,N-dimethylformamide (2 mL) 5-Chloro-6-oxy-1,6-dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane To the alkane-1-carbonitrile (27, 18 mg, 0.040 mmol) was added potassium carbonate (0.15 g, 1.1 mmol) and 2-(2-bromoethoxy)tetrahydropyran (50 mg, 0.24 mmol). The reaction mixture was heated to 60°C for 16 hours. The reaction was filtered to remove insoluble material and concentrated under reduced pressure. To this material was added dichloromethane (8 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and dissolved in 2 mL of N,N-dimethylformamide. This solution was purified by reverse phase flash column chromatography (30 g C18 column; 0-50% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9% _CH3CN , 0.1% _HCO2 h) Purification. This purification affords ( R )-3-((4-(2-((1-(5-chloro-1-(2-hydroxyethyl)-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl- 1H -pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane Alkane-1-carbonitrile (P-0036). MS (ESI)[M+H ⁺ ] ⁺ =536.3.

實例 13

Example 13

步驟1：製備5-((3R )-3-((4-(4-乙醯基環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H )-酮（P-0070）：向5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，0.10 g，0.22 mmol）、1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)環己-3-烯-1-基]乙酮（0.080 g，0.33 mmol）及二氯(1,1-雙(二苯基膦基)二茂鐵)鈀（II）丙酮加合物（0.020 g，0.020 mmol）於小玻璃瓶中之混合物中添加1,4-二

烷（3 mL）。將小瓶加蓋且用氮氣吹掃5分鐘，且隨後在油浴中在100℃下加熱。添加碳酸鉀水溶液（1 M，0.44 mL，0.44 mmol）且在100℃下加熱混合物150分鐘。將粗反應物濃縮至矽藻土上且藉由正相急驟管柱層析（12 g矽膠管柱，0至80%乙酸乙酯/己烷梯度）純化。此純化提供中間物THP保護之產物。將此物質溶解於二氯甲烷（3 mL）中且用鹽酸（1 M於乙酸乙酯中，2.2 mL，2.2 mmol）處理。隨後在室溫下攪拌反應物2小時。將反應物濃縮且再溶解於乙腈/水（1:1，4 mL）中，且隨後藉由反相急驟管柱層析（30 g C18管柱；5-100% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供5-((3R )-3-((4-(4-乙醯基環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H )-酮（P-0070）。MS (ESI)[M+H⁺ ]⁺ =415.3。Step 1: Preparation of 5-(( 3R )-3-((4-(4-acetylcyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl )-4-Chlorata

-3( 2H )-one (P-0070): To 5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro -2-Tetrahydropyran-2-yl-da

-3-one (4, 0.10 g, 0.22 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)cyclohexane -3-En-1-yl]ethanone (0.080 g, 0.33 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct (0.020 g, 0.020 mmol) was added to the mixture in a small glass vial with 1,4-di

alkane (3 mL). The vial was capped and purged with nitrogen for 5 minutes, and then heated at 100°C in an oil bath. Aqueous potassium carbonate (1 M, 0.44 mL, 0.44 mmol) was added and the mixture was heated at 100 °C for 150 min. The crude reaction was concentrated onto celite and purified by normal phase flash column chromatography (12 g silica gel column, 0 to 80% ethyl acetate/hexane gradient). This purification provides the intermediate THP protected product. This material was dissolved in dichloromethane (3 mL) and treated with hydrochloric acid (1 M in ethyl acetate, 2.2 mL, 2.2 mmol). The reaction was then stirred at room temperature for 2 hours. The reaction was concentrated and redissolved in acetonitrile/water (1:1, 4 mL), and then by reverse phase flash column chromatography (30 g C18 column; 5-100% B; A: 99.9% H 2O, 0.1% _{HCO2H ;} B: 99.9% _CH3CN , 0.1% _HCO2H ) purification. This purification provides 5-(( 3R )-3-((4-(4-acetylcyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl) -4-Chlorata

-3( 2H )-one (P-0070). MS (ESI)[M+H ⁺ ] ⁺ =415.3.

實例 14

Example 14

步驟1：製備(R )-4-氯-5-(3-((4-(2,2-二氟-7-氮雜螺[3.5]壬烷-7-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0024）：將5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，0.10 g，0.22 mmol）、2,2-二氟-7-氮雜螺[3.5]壬烷鹽酸鹽（0.070 g，0.33 mmol）、ruphos鈀環GEN 4（0.040 g，0.040 mmol）三級丁醇鈉（0.060 g，0.66 mmol）及甲苯（2 mL）添加至微波小瓶中。隨後將小瓶加蓋，用氮氣吹掃且在微波反應器中加熱至150℃持續45分鐘。將粗反應物濃縮至矽藻土上且藉由反相急驟管柱層析（30 g C18管柱；5-80% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供中間物THP保護之產物。將此物質溶解於二氯甲烷（2 mL）中且用鹽酸（1 M於乙酸乙酯中，1.0 mL，1.0 mmol）處理。隨後在室溫下攪拌反應物90分鐘。將反應物濃縮且再溶解於乙腈/水（1:1，2 mL）中，且隨後藉由反相急驟管柱層析（30 g C18管柱；5-80% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供(R )-4-氯-5-(3-((4-(2,2-二氟-7-氮雜螺[3.5]壬烷-7-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0024）。MS (ESI)[M+H⁺ ]⁺ =452.2。Step 1: Preparation of ( R )-4-chloro-5-(3-((4-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl) oxy)pyrrolidin-1-yl)pyridine

-3( 2H )-one (P-0024): 5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro -2-Tetrahydropyran-2-yl-da

-3-one (4, 0.10 g, 0.22 mmol), 2,2-difluoro-7-azaspiro[3.5]nonane hydrochloride (0.070 g, 0.33 mmol), ruphos palladium ring GEN 4 (0.040 g , 0.040 mmol) sodium tertiary butoxide (0.060 g, 0.66 mmol) and toluene (2 mL) were added to a microwave vial. The vial was then capped, purged with nitrogen and heated to 150°C in a microwave reactor for 45 minutes. The crude reaction was concentrated onto celite and purified by reverse phase flash column chromatography (30 g C18 column; 5-80% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % _CH3CN , 0.1% _HCO2H ). This purification provides the intermediate THP protected product. This material was dissolved in dichloromethane (2 mL) and treated with hydrochloric acid (1 M in ethyl acetate, 1.0 mL, 1.0 mmol). The reaction was then stirred at room temperature for 90 minutes. The reaction was concentrated and redissolved in acetonitrile/water (1:1, 2 mL), and then by reverse phase flash column chromatography (30 g C18 column; 5-80% B; A: 99.9% H 2O, 0.1% _{HCO2H ;} B: 99.9% _CH3CN , 0.1% _HCO2H ) purification. This purification provides ( R )-4-chloro-5-(3-((4-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)oxy base)pyrrolidin-1-yl)pyridine

-3( 2H )-one (P-0024). MS (ESI)[M+H ⁺ ] ⁺ =452.2.

實例 15

Example 15

步驟1：製備4-氯-5-((3R )-3-((4-(8-甲基-3,8-二氮雜雙環[3.2.1]辛烷-3-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0004）：將5-[(3R )-3-[(4-溴-2-吡啶基)氧基]吡咯啶-1-基]-4-氯-2-四氫哌喃-2-基-嗒

-3-酮（4，0.10 g，0.22 mmol）、8-甲基-3,8-二氮雜雙環[3.2.1]辛烷鹽酸鹽（0.054 g，0.33 mmol）、三級丁醇鈉（0.084 g，0.88 mmol）、ruphos鈀環GEN 4（0.037 g，0.044 mmol）及甲苯（2 mL）添加至微波小瓶中。隨後將小瓶加蓋，用氮氣吹掃且在微波反應器中加熱至150℃持續30分鐘。將粗反應物濃縮至矽藻土上且藉由反相急驟管柱層析（30 g C18管柱；5-80% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供中間物THP保護之產物。將此物質溶解於二氯甲烷（1 mL）中且用鹽酸（1 M於乙酸乙酯中，0.5 mL，0.5 mmol）處理。隨後在室溫下攪拌反應物60分鐘。將反應物濃縮且再溶解於乙腈/水（1:1，2 mL）中，且隨後藉由反相急驟管柱層析（15 g C18管柱；5-80% B；A：99.9% H₂ O，0.1% HCO₂ H；B：99.9% CH₃ CN，0.1% HCO₂ H）純化。此純化提供4-氯-5-((3R )-3-((4-(8-甲基-3,8-二氮雜雙環[3.2.1]辛烷-3-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H )-酮（P-0004）。MS (ESI)[M+H⁺ ]⁺ =417.3。Step 1: Preparation of 4-chloro-5-(( 3R )-3-((4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridine- 2-yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0004): 5-[( 3R )-3-[(4-bromo-2-pyridyl)oxy]pyrrolidin-1-yl]-4-chloro -2-Tetrahydropyran-2-yl-da

-3-one (4, 0.10 g, 0.22 mmol), 8-methyl-3,8-diazabicyclo[3.2.1]octane hydrochloride (0.054 g, 0.33 mmol), sodium tertiary butoxide (0.084 g, 0.88 mmol), ruphos palladium ring GEN 4 (0.037 g, 0.044 mmol) and toluene (2 mL) were added to a microwave vial. The vial was then capped, purged with nitrogen and heated to 150°C in a microwave reactor for 30 minutes. The crude reaction was concentrated onto celite and purified by reverse phase flash column chromatography (30 g C18 column; 5-80% B; A: 99.9% _H2O , 0.1% _HCO2H ; B: 99.9 % _CH3CN , 0.1% _HCO2H ). This purification provides the intermediate THP protected product. This material was dissolved in dichloromethane (1 mL) and treated with hydrochloric acid (1 M in ethyl acetate, 0.5 mL, 0.5 mmol). The reaction was then stirred at room temperature for 60 minutes. The reaction was concentrated and redissolved in acetonitrile/water (1:1, 2 mL), and then by reverse phase flash column chromatography (15 g C18 column; 5-80% B; A: 99.9% H 2O, 0.1% _{HCO2H ;} B: 99.9% _CH3CN , 0.1% _HCO2H ) purification. This purification provides 4-chloro-5-(( 3R )-3-((4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridine-2 -yl)oxy)pyrrolidin-1-yl)da

-3( 2H )-one (P-0004). MS (ESI)[M+H ⁺ ] ⁺ =417.3.

以下列舉之表1中之所有化合物可以根據本發明中所描述之合成實例及藉由進行熟習此項技術者能夠以商業或以其他方式獲得之起始物質之任何必需取代而製得。表 1 P# 結構 名稱 （MH）+ P-0001

(R)-(1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)胺基甲酸丁酯 515.3    P-0002

(R)-4-氯-5-(3-((4-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 442.3    P-0003

(R)-4-氯-5-(3-((4-(4-異丙基哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.3    P-0004

4-氯-5-((3R)-3-((4-(8-甲基-3,8-二氮雜雙環[3.2.1]辛基-3-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 417.3    P-0005

(R)-4-氯-5-(3-((4-(1-((3-甲基氧雜環丁烷-3-基)甲基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 460.3    P-0006

4-氯-5-((3S,4S)-3-((4-(1-(1,3-二羥基丙-2-基)-3,5-二甲基-1H-吡唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 541.2    P-0007

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基-1-(氧雜環丁烷-3-基)-1H-吡唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 523.3    P-0008

(R)-4-氯-5-(3-((4-(1-甲基哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 390.3    P-0009

4-氯-5-((3R)-3-((4-(3-甲基哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 390.3    P-0010

(R)-4-氯-5-(3-((4-(1-(2-羥基-2-甲基丙基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 448.3    P-0011

4-氯-5-((3R)-3-((4-(1-(3,3,3-三氟-2-羥丙基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 488.2    P-0012

5-((3R)-3-((4-(8-氮雜雙環[3.2.1]辛烷-3-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 402.3    P-0013

5-((3R)-3-((4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 403.3    P-0014

(R)-4-氯-5-(3-((6-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 504.3    P-0015

4-氯-5-((3S,4S)-3-氟-4-((4-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 521.2    P-0016

(R)-4-氯-5-(3-((4-(1-(2-羥基乙醯基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 434.3    P-0017

(R)-4-氯-5-(3-((4-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 503.3    P-0018

4-氯-5-((3R)-3-((4-(吡咯啶-3-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 362.2    P-0019

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基-1-(氧雜環丁烷-3-基)-1H-吡唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 479.2    P-0020

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(氧雜環丁烷-3-基)-1H-吡唑-4-基)-5-氟吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 505.2    P-0021

4-氯-5-((3S,4S)-3-氟-4-((4-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 477.2    P-0022

(R)-4-氯-5-(3-((4-(1-環丙基-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 427.3    P-0023

(R)-4-氯-2-(2-羥乙基)-5-(3-((4-(哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 420.3    P-0024

(R)-4-氯-5-(3-((4-(2,2-二氟-7-氮雜螺[3.5]壬烷-7-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 452.2    P-0025

(R)-2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)-N-(四氫-2H-哌喃-4-基)異菸鹼醯胺 420.0    P-0026

(R)-4-氯-5-(3-((4-(1-環丁基-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 441.4    P-0027

(R)-4-氯-5-(3-((4-(1-異丙基-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 429.4 P-0028

3-(2-(((R)-1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氮雜雙環[3.2.1]辛烷-8-甲酸甲酯 460.3    P-0029

(R)-4-氯-5-(3-((1'-(甲磺醯基)-1',2',3',6'-四氫-[4,4'-二吡啶]-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 452.2    P-0030

(R)-2-(1-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)哌啶-4-基)乙腈 415.3    P-0031

(R)-4-氯-5-(3-((4-(4-羥環己基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 391.3    P-0032

(R)-4-氯-5-(3-((4-(2,5-二氫-1H-吡咯-3-基)吡啶-2-基)吡咯啶-1-基)嗒

-3(2H)-酮 360.2    P-0033

(R)-2-(3-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)氧雜環丁烷-3-基)乙腈 482.3    P-0034

(R)-3-((4-(2-((1-(5-氯-1-(2-羥乙基)-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈 536.3    P-0035

(R)-2-(1-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)環丁基)乙醯胺 498.3    P-0036

(R)-2-(1-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)環丁基)乙腈 480.3    P-0037

(R)-4-氯-5-(3-((6-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 460.3    P-0038

(R)-4-氯-5-(3-((4-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 459.3    P-0039

4-氯-5-((3R)-3-((4-(3,5-二甲基-1-(3,3,3-三氟-2-羥丙基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 499.3    P-0040

(R)-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)-N-環丙基乙醯胺 484.4    P-0041

(R))-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)-N-甲基乙醯胺 458.4    P-0042

4-氯-5-((3R)-3-((4-(3,5-二甲基-1-((四氫呋喃-2-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 471.4    P-0043

4-氯-5-((3R)-3-((4-(3,5-二甲基-1-((四氫-2H-哌喃-3-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 485.4    P-0044

(R)-3-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)丙腈 440.4    P-0045

(R)-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)乙酸 445.2    P-0046

(R)-4-(2-((1-(5-氯-1-(2-羥乙基)-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)環己烷-1-腈 444.3    P-0047

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)環己烷-1-羧酸 419.3    P-0048

(R)-4-氯-5-(3-((4-(1-(2,2,2-三氟乙基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 458.3    P-0049

8-(2-(((R)-1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-8-氮雜雙環[3.2.1]辛烷-3-腈 427.2    P-0050

4-(2-(((R)-1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)環己-3-烯-1-羧酸 417.2    P-0051

(R)-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-(三氟甲基)嗒

-3(2H)-酮 422.0    P-0052

(R)-3-((4-(6-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)嘧啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)環丁烷-1-腈 481.0    P-0053

(R)-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)雙環[1.1.1]戊烷-1-腈 492.3    P-0054

(R)-4-氯-5-(3-((4-(1-((3-乙基氧雜環丁烷-3-基)甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 485.3    P-0055

(R)-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)環丁烷-1-甲酸甲酯 513.3    P-0056

(R)-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)環丁烷-1-甲醯胺 498.3    P-0057

(R)-3-((4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)甲基)環丁烷-1-腈 480.3    P-0058

(R)-4-氯-5-(3-((4-(1-(環丙烷羰基)哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 444.3    P-0059

(R)-5-(3-((4-(4-胺基環己基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 390.2    P-0060

(R)-5-(3-((4-(4-乙醯基環己基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 417.2    P-0061

(R)-4-氯-5-(3-((6-(3,5-二甲基-1-(氧雜環丁烷-3-基甲基)-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 458.3    P-0062

(R)-4-氯-5-(3-((4-(1-乙基-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 459.3    P-0063

(R)-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-3-側氧基-2,3-二氫嗒

-4-腈 379.3    P-0064

4-氯-5-((3R)-3-((4-(1-(4-氯-2-羥基丁基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 537.2    P-0065

(R)-4-氯-5-(3-((4-(1-((3-羥基氧雜環丁烷-3-基)甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 473.2    P-0066

(R)-4-溴-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 431.9    P-0067

5-((3R)-3-((4-(4-胺基環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 388.3    P-0068

5-((3R)-3-((4-(4-乙醯基環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 415.3    P-0069

4-氯-5-((3R)-3-((4-(1-(1-氯-3-羥基丙-2-基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 479.2    P-0070

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(氧雜環丁烷-3-基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 443.3    P-0071

(R)-4-氯-5-(3-((4-(哌啶-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 376.3    P-0072

(R)-4-氯-5-(3-((4-(四氫-2H-哌喃-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 377.3    P-0073

(R)-4-氯-5-(3-((4-環戊基吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 361.2    P-0074

(R)-1-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)哌啶-4-腈 401.2    P-0075

(R)-4-氯-5-(3-((1',2',3',6'-四氫-[4,4'-二吡啶]-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 374.2    P-0076

(R)-4-氯-5-(3-((4-(1-(2-羥乙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 431.3    P-0077

(R)-4-氯-5-(3-((4-(1-乙基-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 415.3    P-0078

(R)-4-氯-5-(3-((4-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 375.2    P-0079

(R)-4-氯-5-(3-((4-(2,2-二甲基吡咯啶-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 390.3    P-0080

(R)-4-氯-5-(3-((4-(2,2-二甲基哌

-1-基)吡啶-2-基氧基)吡咯啶-1-基)嗒

-3(2H)-酮 405.2    P-0081

(R)-4-氯-5-(3-((4-(2-甲基-4-(甲磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 461.1    P-0082

(R)-5-(3-((4-(2-氧雜-7-氮雜螺[3.5]壬烷-7-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 418.2    P-0083

(R)-4-氯-5-(3-((4-(4-(氯甲基)-4-(羥甲基)哌啶-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 454.0    P-0084

(R)-4-氯-5-(3-((4-(環戊-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 359.1    P-0085

(R)-4-氯-5-(3-((4-環己基吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 375.2 P-0086

4-氯-5-((3R)-3-((4-(3,5-二甲基-1-(氧雜環丁烷-2-基甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 457.1    P-0087

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(氧雜環丁烷-3-基甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 457.1    P-0088

4-氯-5-((3R)-3-((4-(1-(1-羥基-3-碘基丙-2-基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 570.9    P-0089

(R)-5-(3-((2-胺基-6-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 417.2    P-0090

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(3-羥丙基)嗒

-3(2H)-酮 446.1    P-0091

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)環己烷-1-腈 400.1    P-0092

4-氯-5-((3R)-3-((4-(3-甲基

啉基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 392.1    P-0093

4-氯-5-((3R)-3-((4-(2-甲基吡咯啶-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 376.1    P-0094

4-氯-5-((3R)-3-((4-(2-甲基哌啶-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 390.1    P-0095

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(3-甲基氧雜環丁烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 471.1    P-0096

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基-1-((3-甲基氧雜環丁烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 489.1    P-0097

(R)-2-(3-羥丙基)-3-側氧基-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2,3-二氫嗒

-4-腈 450.2    P-0098

(R)-2-(2-羥乙基)-3-側氧基-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2,3-二氫嗒

-4-腈 436.2    P-0099

(R)-4-氯-5-(3-((4-(4,4-二甲基環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 401.1    P-0100

4-(2-(((R)-1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)環己-3-烯-1-腈 （M+H）+    P-0101

(R)-4-氯-2-(2-羥乙基)-5-(3-((3-((3-異丙基-1-甲基-1H-吡唑-5-基)胺基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 474.0    P-0102

(R)-4-氯-5-(3-((3-((4,4-二氟環己基)胺基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 470.0    P-0103

5-((R)-3-((4-((S)-4-乙醯基-2-甲基哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 433.0    P-0104

5-((R)-3-((4-((R)-4-乙醯基-2-甲基哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 432.9    P-0105

(R)-4-氯-5-(3-((3-((2-異丙基-4-甲基吡啶-3-基)胺基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 441.0    P-0106

(R)-4-氯-2-(2-羥乙基)-5-(3-((4-(5-甲氧基-1-甲基-1H-吲哚-2-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 496.0    P-0107   

4-氯-5-((R)-3-((4-((1R,5S)-3,3-二氟-8-氮雜雙環[3.2.1]辛烷-8-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 482.0    P-0108

(R)-4-氯-5-(3-((4-(5-甲氧基-1-甲基-1H-吲哚-2-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 452.0    P-0109

(R)-4-氯-5-(3-((3-((3-異丙基-1-甲基-1H-吡唑-5-基)胺基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 430.0    P-0110

(R)-4-氯-5-(3-((3-((4,4-二氟環己基)胺基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 426.0    P-0111   

4-氯-5-((R)-3-((4-((1R,5S)-3,3-二氟-8-氮雜雙環[3.2.1]辛烷-8-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 437.9    P-0112

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-((3-甲基氧雜環丁烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 515.0    P-0113

(R)-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 367.2    P-0114

(R)-3-側氧基-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2,3-二氫嗒

-4-腈 392.0    P-0115

(R)-4-氯-5-(3-((5-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 463.1    P-0116

(R)-4-氯-5-(3-((4-(環己-1-烯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 373.1    P-0117

(R)-4-氯-5-(3-((5-氟-2-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.3    P-0118

(R)-4-氯-5-(3-((2-(3,5-二甲基異

唑-4-基)-5-氟吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 406.2    P-0119

4-氯-5-((3S,4S)-3-氟-4-((2-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 463.2    P-0120

4-氯-5-((3S,4S)-3-((2-(3,5-二甲基異

唑-4-基)吡啶-4-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 450.1    P-0121

4-氯-5-((3S,4S)-3-氟-4-((2-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.2    P-0122

4-氯-5-((3S,4S)-3-((2-(3,5-二甲基異

唑-4-基)吡啶-4-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 406.2    P-0123

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 450.0    P-0124

(R)-4-氯-2-(2-羥乙基)-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 463.0    P-0125

(R)-4-氯-5-(3-((6-(3-(甲氧基甲基)-5-甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.0    P-0126

4-氯-2-(2-羥丙基)-5-((R)-3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 459.1    P-0127

(R)-4-氯-2-(3-羥丙基)-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)吡咯啶-1-基)嗒

-3(2H)-酮 459.1    P-0128

(R)-4-氯-2-(2-羥乙基)-5-(3-((6-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 446.3    P-0129

4-氯-2-(2,3-二羥丙基)-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 498.0    P-0130

(R)-4-氯-5-(3-((4-(1-((3-氟氧雜環丁烷-3-基)甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 475.0    P-0131

4-氯-2-(2,3-二羥丙基)-5-((R)-3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 474.9    P-0132

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮    468.3    P-0133

(R)-4-氯-5-(3-((6-氟-4-(1-((3-氟氧雜環丁烷-3-基)甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 493.0    P-0134

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)-5-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 424.1    P-0135

(R)-4-氯-2-(2-羥乙基)-5-(3-((2-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 445.1    P-0136

(R)-4-氯-5-(3-((2-(3,5-二甲基異

唑-4-基)吡啶-4-氧)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 432.2    P-0137

(R)-4-氯-5-(3-((2-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 401.1 99    P-0138

(R)-4-氯-5-(3-((2-(3,5-二甲基異

唑-4-基)吡啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 388.2 P-0139

(R)-4-氯-5-(3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)-2-(3-羥丙基)嗒

-3(2H)-酮 447.0    P-0140

4-氯-2-(2,3-二羥丙基)-5-((R)-3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 463.0    P-0141

(R)-2-(2-胺乙基)-4-氯-5-(3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 432.3    P-0142

4-氯-5-((3S,4S)-3-氟-4-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 463.3    P-0143

(R)-4-氯-2-(2-羥乙基)-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 444.95    P-0144

4-氯-5-((3S,4S)-3-氟-4-((6-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 463.95 99    P-0145

4-氯-5-((3S,4S)-3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 451.0    P-0146

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)-5-氟吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 450.1    P-0147

4-氯-5-((3S,4S)-3-氟-4-((6-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 420.0    P-0148

4-氯-5-((3S,4S)-3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 407.0       P-0149

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)-5-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 406.0    P-0150

(R)-4-氯-5-(3-((4-(3-(甲氧基甲基)-5-甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 418.0    P-0151

(R)-4-氯-5-(3-((6-氟-4-(5-甲基-1-((3-甲基氧雜環丁烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 475.9    P-0152

(R)-4-氯-5-(3-((4-(1-(環丙基甲基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 459.0    P-0153

(R)-4-氯-5-(3-((4-(2,3-二甲基-1H-吲哚-1-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 454.0    P-0154

(R)-4-氯-5-(3-((6-氟-4-(1-((3-氟氮雜環丁烷-3-基)甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 492.0    P-0155

(R)-4-氯-5-(3-((4-(4-氯-1-甲基-1H-吡唑-5-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 407.0    P-0156

(R)-4-氯-5-(3-((5-(1,3,5-三甲基-1H-吡唑-4-基)嗒

-3-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 402.0    P-0157

(R)-4-氯-5-(3-((6-(1,3,5-三甲基-1H-吡唑-4-基)嗒

-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 402.0    P-0158

(R)-4-氯-5-(3-((5-(3,5-二甲基異

唑-4-基)嗒

-3-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 389.0    P-0159

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(2-(吡咯啶-1-基)乙基)-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 502.0    P-0160

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(2-

啉基乙基)-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 517.95    P-0161

(R)-4-氯-5-(3-((4-(1-(2-(二甲胺基)乙基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 476.0    P-0162

(R)-4-氯-5-(3-((5-(3,5-二甲基異

唑-4-基)吡啶-3-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 388.0    P-0163

5,5'-((3R,3'R)-(吡啶-3,5-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯嗒

-3(2H)-酮) 506.0    P-0164

(R)-5-(3-((4-(3,5-二甲基-1-丙基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 413.1    P-0165

   (R)-4-氯-5-(3-((4-(3,5-二甲基-1-丙基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 447.0    P-0166

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(3,3,3-三氟丙基)-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 500.95    P-0167

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-(2,2,2-三氟乙基)-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 487.0    P-0168

(R)-4-氯-5-(3-((5-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-3-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 401.0    P-0169

(R)-4-氯-5-(3-((4-(1-(2,2-二氟乙基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 469.0    P-0170

(R)-4-氯-5-(3-((4-(1-(二氟甲基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 437.0    P-0171

(R)-4-氯-5-(3-((5-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.0    P-0172

(R)-4-氯-5-(3-((4-(1,4-二甲基-1H-1,2,3-***-5-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 406.1    P-0173

(R)-4-氯-5-(3-((6-氟-4-(1-甲基-1H-咪唑-5-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 391.1    P-0174

(R)-4-氯-5-(3-((4-(2,4-二甲基噻唑-5-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 422.0    P-0175

(R)-4-氯-5-(3-((4-(1,4-二甲基-1H-吡唑-5-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 405.1    P-0176

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮      432.4    P-0177

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 450.2       P-0178

(R)-4-氯-5-(3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮      433.0         P-0179

4-氯-5-((3S,4S)-3-氟-4-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 419.0    P-0180

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 406.0    P-0181

(R)-4-氯-5-(3-((6-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 402.0    P-0182

R)-4-氯-5-(3-((6-(3,5-二甲基異

唑-4-基)嘧啶-4-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 389.0    P-0183

(R)-4-氯-5-(3-((4-(1-(環丁基甲基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 473.0    P-0184

(R)-4-氯-5-(3-((4-(3,5-二甲基-1-((3-甲基氧雜環丁烷-3-基)甲基)-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 489.3    P-0185

4-氯-5-((3R)-3-((4-(1-(3-氯-2-(羥甲基)-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 525.0    P-0186

(R)-4-氯-5-(3-((6-氟-4-(1-(2-羥基-2-甲基丙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 477.0    P-0187

(R)-4-氯-5-(3-((4-(1-((3,3-二氟環丁基)甲基)-3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 509.0    P-0188

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)-6-氟吡啶-2-氧)氧基)-4-氟吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 468.0    P-0189

4-氯-5-((3S,4S)-3-((4-(3,5-二甲基異

唑-4-基)-6-氟吡啶-2-基)氧基)-4-氟吡咯啶-1-基)嗒

-3(2H)-酮 424.0    P-0190

4-氯-5-((3S,4S)-3-氟-4-((6-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 481.3    P-0191

4-氯-5-((3S,4S)-3-氟-4-((6-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 437.0    P-0192

(R)-4-氯-5-(3-((6-氟-4-(1-(2-羥乙基)-3,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 449.0    P-0193

(R)-4-氯-5-(3-((4-(3,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 405.0    P-0194

(R)-4-氯-5-(3-((4-(1,5-二甲基-1H-吡唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 405.0    P-0195

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)-6-氟吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 406.0    P-0196

(R)-4-氯-5-(3-(3-(1,5-二甲基-1H-吡唑-4-基)苯氧基)吡咯啶-1-基)嗒

-3(2H)-酮 386.0    P-0197

(R)-4-氯-5-(3-(3-(1,3-二甲基-1H-吡唑-4-基)苯氧基)吡咯啶-1-基)嗒

-3(2H)-酮 386.0    P-0198

(R)-4-氯-5-(3-(3-(1,3,5-三甲基-1H-吡唑-4-基)苯氧基)吡咯啶-1-基)嗒

-3(2H)-酮 400.0    P-0199

(R)-4-氯-5-(3-((6-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)-2-(2-羥乙基)嗒

-3(2H)-酮 463.9    P-0200

(R)-4-氯-5-(3-((6-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮       P-0201

(R)-4-氯-5-(3-((4-(3,5-二甲基異

唑-4-基)吡啶-2-基)吡咯啶-1-基)嗒

-3(2H)-酮 388.0    P-0202

(R)-3-氯-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-乙基苯磺醯胺 509.9    P-0203

(R)-4-氯-5-(3-((4-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 401.1    P-0204

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)丙烷-1-磺醯胺 508.0    P-0205

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)異丁醯胺 472.0    P-0206

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)環戊烷甲醯胺 498.0    P-0207

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基-3,5-二氟苯磺醯胺 523.9    P-0208

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3,5-二氟-N-丙基苯磺醯胺 526.0    P-0209

(R)-4-氯-5-(3-((4-(1,5-二甲基-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 387.1    P-0210

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-甲苯基)環丙烷磺醯胺。 502.0    P-0211

(R)-1-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)-3-環丙基脲 485.0    P-0212

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)環丁甲醯胺 484.0    P-0213

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)乙醯胺 444.0    P-0214

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)苯甲醯胺 506.0    P-0215

5,5'-((3R,3'R)-([4,4'-聯吡啶]-2,2'-二基雙(氧基))雙(吡咯啶-3,1-二基))雙(4-氯嗒

-3(2H)-酮) 583.0    P-0216

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)-6-氟吡啶-4-基)-3-甲基-N-丙基苯磺醯胺 522.0    P-0217

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)-6-氟吡啶-4-基)-N-環丙基-3-甲基苯磺醯胺 522.0    P-0218

(R)-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)乙酸甲酯 459.0    P-0219

(R)-2-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟苯基)乙酸 444.95    P-0220

(R)-5-(3-((4-(4-胺基-2-氟苯基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 402.1    P-0221

R)-N-(1-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)哌啶-4-基)環丙烷磺醯胺 495.0    P-0222

(R)-N-(1-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)哌啶-4-基)環丙烷甲醯胺 459.0    P-0223

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-丙基苯磺醯胺 490.0    P-0224

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基-3-氟-5-甲基苯磺醯胺 520.0    P-0225

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-氟-5-甲基-N-丙基苯磺醯胺 522.0 P-0226

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-丙基哌

-1-磺醯胺 498.0    P-0227

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基-3-甲氧基苯磺醯胺 518.0    P-0228

(R)-4-氯-5-(3-((4-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 431.1    P-0229

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基哌

-1-磺醯胺 496.0    P-0230

(R)-3-氯-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基苯磺醯胺 521.9    P-0231

(R)-4-氯-5-(3-((6-(三氟甲基)-[3,4'-二吡啶]-2'-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 437.95    P-0232

(R)-4-氯-5-(3-((4-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 470.9    P-0233

(R)-3-氯-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-丙基苯磺醯胺 523.9    P-0234

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基-3-氟苯磺醯胺 506.0    P-0235

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基-3-甲基苯磺醯胺 502.0    P-0236

(R)-4-氯-5-(3-((4-(4-(三氟甲基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 437.0    P-0237

(R)-4-氯-5-(3-((4-(4-(三氟甲氧基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 453.0    P-0238

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)-5-氟吡啶-4-基)-N-環丙基苯磺醯胺 505.9    P-0239

(R)-4-氯-5-(3-((4-(4-(丙基磺醯基)哌

-1-基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 483.1    P-0240

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-3-甲基-N-丙基苯磺醯胺    504.0    P-0241

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-(4-氟苯基)苯磺醯胺 541.9    P-0242

(R)-N-丁基-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)苯磺醯胺 504.0    P-0243

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-乙基苯磺醯胺 475.9    P-0244

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-甲基苯磺醯胺 462.0    P-0245

(R)-N-(4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)苯基)環丙烷磺醯胺 488.0    P-0246

(R)-4-氯-5-(3-((4-(4-(吡咯啶-1-基磺醯基)苯基)吡啶-2-基)吡咯啶-1-基)嗒

-3(2H)-酮 502.0    P-0247

(R)-4-(2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基苯磺醯胺 487.9    P-0248

(R)-4-氯-5-(3-((5-氯-4-(4-(吡咯啶-1-基磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 535.9    P-0249

(R)-4-氯-5-(3-((5-氯-4-(4-(哌啶-1-基磺醯基)苯基)吡啶-2-基)氧基)吡咯啶-1-基)嗒

-3(2H)-酮 549.9    P-0250

(R)-3-(5-氯-2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基苯磺醯胺 345.0    P-0251

(R)-4-(5-氯-2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)吡啶-4-基)-N-環丙基苯磺醯胺 521.9    P-0252

(R)-5-(3-((4-(1H-吡咯-1-基)吡啶-2-基)氧基)吡咯啶-1-基)-4-氯嗒

-3(2H)-酮 358.0    P-0253

(R)-2-((1-(5-氯-6-側氧基-1,6-二氫嗒

-4-基)吡咯啶-3-基)氧基)-6-(吡咯啶-1-基)異菸鹼腈 387.0    生物測試方法 All compounds listed in Table 1 below can be prepared according to the synthetic examples described in this invention and by making any necessary substitutions of starting materials commercially or otherwise available to those skilled in the art.surface 1 P# structure name (MH)+ P-0001

(R)-(1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)carbamate 515.3 P-0002

(R)-4-Chloro-5-(3-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 442.3 P-0003

(R)-4-Chloro-5-(3-((4-(4-isopropylpiperidine)

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 419.3 P-0004

4-Chloro-5-((3R)-3-((4-(8-methyl-3,8-diazabicyclo[3.2.1]octyl-3-yl)pyridin-2-yl)oxy base)pyrrolidin-1-yl)pyridine

-3(2H)-one 417.3 P-0005

(R)-4-Chloro-5-(3-((4-(1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)pyridine-2- yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 460.3 P-0006

4-Chloro-5-((3S,4S)-3-((4-(1-(1,3-dihydroxypropan-2-yl)-3,5-dimethyl-1H-pyrazole-4 -yl)-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 541.2 P-0007

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl )-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 523.3 P-0008

(R)-4-Chloro-5-(3-((4-(1-methylpiperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 390.3 P-0009

4-Chloro-5-((3R)-3-((4-(3-methylpiperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 390.3 P-0010

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 448.3 P-0011

4-Chloro-5-((3R)-3-((4-(1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl)pyridin-2-yl)oxy base)pyrrolidin-1-yl)pyridine

-3(2H)-one 488.2 P-0012

5-((3R)-3-((4-(8-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4- Chloride

-3(2H)-one 402.3 P-0013

5-((3R)-3-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl) -4-Chlorata

-3(2H)-one 403.3 P-0014

(R)-4-Chloro-5-(3-((6-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazol-4-yl) pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 504.3 P-0015

4-Chloro-5-((3S,4S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyridine azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 521.2 P-0016

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxyacetyl)piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl )despair

-3(2H)-one 434.3 P-0017

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazol-4-yl) Pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 503.3 P-0018

4-Chloro-5-((3R)-3-((4-(pyrrolidin-3-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 362.2 P-0019

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl )-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 479.2 P-0020

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)- 5-Fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 505.2 P-0021

4-Chloro-5-((3S,4S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyridine oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 477.2 P-0022

(R)-4-Chloro-5-(3-((4-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one 427.3 P-0023

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((4-(piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl )despair

-3(2H)-one 420.3 P-0024

(R)-4-Chloro-5-(3-((4-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)oxy)pyrrole pyridin-1-yl)da

-3(2H)-one 452.2 P-0025

(R)-2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)-N-(tetrahydro-2H-pyran-4-yl)isonicotinamide 420.0 P-0026

(R)-4-Chloro-5-(3-((4-(1-cyclobutyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one 441.4 P-0027

(R)-4-Chloro-5-(3-((4-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one 429.4 P-0028

3-(2-(((R)-1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid methyl ester 460.3 P-0029

(R)-4-Chloro-5-(3-((1'-(methylsulfonyl)-1',2',3',6'-tetrahydro-[4,4'-bipyridine]- 2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 452.2 P-0030

(R)-2-(1-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)piperidin-4-yl)acetonitrile 415.3 P-0031

(R)-4-Chloro-5-(3-((4-(4-hydroxycyclohexyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 391.3 P-0032

(R)-4-Chloro-5-(3-((4-(2,5-dihydro-1H-pyrrol-3-yl)pyridin-2-yl)pyrrolidin-1-yl)da

-3(2H)-one 360.2 P-0033

(R)-2-(3-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)oxetan-3-yl)acetonitrile 482.3 P-0034

(R)-3-((4-(2-((1-(5-Chloro-1-(2-hydroxyethyl)-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane -1-Nitrile 536.3 P-0035

(R)-2-(1-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)cyclobutyl)acetamide 498.3 P-0036

(R)-2-(1-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)cyclobutyl)acetonitrile 480.3 P-0037

(R)-4-Chloro-5-(3-((6-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazol-4-yl) pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 460.3 P-0038

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazol-4-yl) Pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 459.3 P-0039

4-Chloro-5-((3R)-3-((4-(3,5-dimethyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole- 4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 499.3 P-0040

(R)-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-cyclopropylacetamide 484.4 P-0041

(R))-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-methylacetamide 458.4 P-0042

4-Chloro-5-((3R)-3-((4-(3,5-dimethyl-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 471.4 P-0043

4-Chloro-5-((3R)-3-((4-(3,5-dimethyl-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazole -4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 485.4 P-0044

(R)-3-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)propionitrile 440.4 P-0045

(R)-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetic acid 445.2 P-0046

(R)-4-(2-((1-(5-Chloro-1-(2-hydroxyethyl)-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)cyclohexane-1-carbonitrile 444.3 P-0047

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)cyclohexane-1-carboxylic acid 419.3 P-0048

(R)-4-Chloro-5-(3-((4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 458.3 P-0049

8-(2-(((R)-1-(5-Chloro-6-oxy-1,6-dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-8-azabicyclo[3.2.1]octane-3-carbonitrile 427.2 P-0050

4-(2-(((R)-1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)cyclohex-3-ene-1-carboxylic acid 417.2 P-0051

(R)-5-(3-((4-(3,5-Dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine

-3(2H)-one 422.0 P-0052

(R)-3-((4-(6-(((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyrimidin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclobutane-1-carbonitrile 481.0 P-0053

(R)-3-((4-(2-(((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentane -1-Nitrile 492.3 P-0054

(R)-4-Chloro-5-(3-((4-(1-((3-ethyloxetan-3-yl)methyl)-3,5-dimethyl-1H- Pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 485.3 P-0055

(R)-3-((4-(2-(((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclobutane-1-carboxylic acid methyl ester 513.3 P-0056

(R)-3-((4-(2-(((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclobutane-1-carboxylate amine 498.3 P-0057

(R)-3-((4-(2-(((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)cyclobutane-1-carbonitrile 480.3 P-0058

(R)-4-Chloro-5-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 444.3 P-0059

(R)-5-(3-((4-(4-Aminocyclohexyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 390.2 P-0060

(R)-5-(3-((4-(4-Acetylcyclohexyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 417.2 P-0061

(R)-4-Chloro-5-(3-((6-(3,5-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl )pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 458.3 P-0062

(R)-4-Chloro-5-(3-((4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrole pyridin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 459.3 P-0063

(R)-5-(3-((4-(3,5-Dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-3-oxy-2,3-dihydropyridine

-4-Nitrile 379.3 P-0064

4-Chloro-5-((3R)-3-((4-(1-(4-Chloro-2-hydroxybutyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 537.2 P-0065

(R)-4-Chloro-5-(3-((4-(1-((3-hydroxyoxetan-3-yl)methyl)-3,5-dimethyl-1H-pyridine oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 473.2 P-0066

(R)-4-Bromo-5-(3-((4-(3,5-dimethyliso

oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 431.9 P-0067

5-((3R)-3-((4-(4-Aminocyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 388.3 P-0068

5-((3R)-3-((4-(4-Acetylcyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloro despair

-3(2H)-one 415.3 P-0069

4-Chloro-5-((3R)-3-((4-(1-(1-Chloro-3-hydroxypropan-2-yl)-3,5-dimethyl-1H-pyrazole-4- yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 479.2 P-0070

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 443.3 P-0071

(R)-4-Chloro-5-(3-((4-(piperidin-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 376.3 P-0072

(R)-4-Chloro-5-(3-((4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 377.3 P-0073

(R)-4-Chloro-5-(3-((4-cyclopentylpyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 361.2 P-0074

(R)-1-(2-((1-(5-Chloro-6-oxo-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)piperidine-4-carbonitrile 401.2 P-0075

(R)-4-Chloro-5-(3-((1',2',3',6'-tetrahydro-[4,4'-dipyridin]-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 374.2 P-0076

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl ) oxy) pyrrolidin-1-yl) pyridine

-3(2H)-one 431.3 P-0077

(R)-4-Chloro-5-(3-((4-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrole pyridin-1-yl)da

-3(2H)-one 415.3 P-0078

(R)-4-Chloro-5-(3-((4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl) despair

-3(2H)-one 375.2 P-0079

(R)-4-Chloro-5-(3-((4-(2,2-Dimethylpyrrolidin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 390.3 P-0080

(R)-4-Chloro-5-(3-((4-(2,2-dimethylpiperidine)

-1-yl)pyridin-2-yloxy)pyrrolidin-1-yl)da

-3(2H)-one 405.2 P-0081

(R)-4-Chloro-5-(3-((4-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl) despair

-3(2H)-one 461.1 P-0082

(R)-5-(3-((4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl) -4-Chlorata

-3(2H)-one 418.2 P-0083

(R)-4-Chloro-5-(3-((4-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)oxy)pyrrole pyridin-1-yl)da

-3(2H)-one 454.0 P-0084

(R)-4-Chloro-5-(3-((4-(cyclopent-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 359.1 P-0085

(R)-4-Chloro-5-(3-((4-cyclohexylpyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 375.2 P-0086

4-Chloro-5-((3R)-3-((4-(3,5-dimethyl-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl )pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 457.1 P-0087

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl )pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 457.1 P-0088

4-Chloro-5-((3R)-3-((4-(1-(1-hydroxy-3-iodopropan-2-yl)-3,5-dimethyl-1H-pyrazole-4 -yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 570.9 P-0089

(R)-5-(3-((2-Amino-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine- 1-Base)-4-Chloro

-3(2H)-one 417.2 P-0090

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(3-hydroxypropyl)pyridine

-3(2H)-one 446.1 P-0091

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)cyclohexane-1-carbonitrile 400.1 P-0092

4-Chloro-5-((3R)-3-((4-(3-methyl

olinyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 392.1 P-0093

4-Chloro-5-((3R)-3-((4-(2-methylpyrrolidin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 376.1 P-0094

4-Chloro-5-((3R)-3-((4-(2-methylpiperidin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 390.1 P-0095

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(3-methyloxetan-3-yl)methyl)-1H-pyridine oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 471.1 P-0096

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyl-1-((3-methyloxetan-3-yl)methyl)- 1H-pyrazol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 489.1 P-0097

(R)-2-(3-hydroxypropyl)-3-oxy-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)-2,3-dihydropyridine

-4-Nitrile 450.2 P-0098

(R)-2-(2-hydroxyethyl)-3-oxy-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)-2,3-dihydropyridine

-4-Nitrile 436.2 P-0099

(R)-4-Chloro-5-(3-((4-(4,4-dimethylcyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidine-1- base)

-3(2H)-one 401.1 P-0100

4-(2-(((R)-1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)cyclohex-3-ene-1-carbonitrile (M+H)+ P-0101

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((3-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)amine yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 474.0 P-0102

(R)-4-Chloro-5-(3-((3-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2- (2-hydroxyethyl)da

-3(2H)-one 470.0 P-0103

5-((R)-3-((4-((S)-4-Acetyl-2-methylpiperidine

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 433.0 P-0104

5-((R)-3-((4-((R)-4-Acetyl-2-methylpiperidine

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 432.9 P-0105

(R)-4-Chloro-5-(3-((3-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridin-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 441.0 P-0106

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((4-(5-methoxy-1-methyl-1H-indol-2-yl)pyridine- 2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 496.0 P-0107   

4-Chloro-5-((R)-3-((4-((1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyridine- 2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 482.0 P-0108

(R)-4-Chloro-5-(3-((4-(5-methoxy-1-methyl-1H-indol-2-yl)pyridin-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 452.0 P-0109

(R)-4-Chloro-5-(3-((3-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy )pyrrolidin-1-yl)pyridine

-3(2H)-one 430.0 P-0110

(R)-4-Chloro-5-(3-((3-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 426.0 P-0111   

4-Chloro-5-((R)-3-((4-((1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyridine- 2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 437.9 P-0112

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1H- Pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 515.0 P-0113

(R)-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 367.2 P-0114

(R)-3-Pendant oxy-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidine -1-Base)-2,3-dihydrogen

-4-Nitrile 392.0 P-0115

(R)-4-Chloro-5-(3-((5-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 463.1 P-0116

(R)-4-Chloro-5-(3-((4-(cyclohex-1-en-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 373.1 P-0117

(R)-4-Chloro-5-(3-((5-fluoro-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one 419.3 P-0118

(R)-4-Chloro-5-(3-((2-(3,5-dimethyliso

oxazol-4-yl)-5-fluoropyridin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 406.2 P-0119

4-Chloro-5-((3S,4S)-3-fluoro-4-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy yl)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 463.2 P-0120

4-Chloro-5-((3S,4S)-3-((2-(3,5-dimethyliso

azol-4-yl)pyridin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 450.1 P-0121

4-Chloro-5-((3S,4S)-3-fluoro-4-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy base)pyrrolidin-1-yl)pyridine

-3(2H)-one 419.2 P-0122

4-Chloro-5-((3S,4S)-3-((2-(3,5-dimethyliso

oxazol-4-yl)pyridin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 406.2 P-0123

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

azol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 450.0 P-0124

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((6-(3-(methoxymethyl)-5-methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 463.0 P-0125

(R)-4-Chloro-5-(3-((6-(3-(methoxymethyl)-5-methyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 419.0 P-0126

4-Chloro-2-(2-hydroxypropyl)-5-((R)-3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 459.1 P-0127

(R)-4-Chloro-2-(3-hydroxypropyl)-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2 -yl)pyrrolidin-1-yl)pyridine

-3(2H)-one 459.1 P-0128

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-4 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 446.3 P-0129

4-Chloro-2-(2,3-dihydroxypropyl)-5-((3S,4S)-3-((4-(3,5-dimethylisopropyl)

oxazol-4-yl)-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 498.0 P-0130

(R)-4-Chloro-5-(3-((4-(1-((3-fluorooxetan-3-yl)methyl)-3,5-dimethyl-1H-pyridine oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 475.0 P-0131

4-Chloro-2-(2,3-dihydroxypropyl)-5-((R)-3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl) Pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 474.9 P-0132

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 468.3 P-0133

(R)-4-Chloro-5-(3-((6-fluoro-4-(1-((3-fluorooxetan-3-yl)methyl)-3,5-dimethyl -1H-Pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 493.0 P-0134

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

oxazol-4-yl)-5-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 424.1 P-0135

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-4 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 445.1 P-0136

(R)-4-Chloro-5-(3-((2-(3,5-dimethyliso

azol-4-yl)pyridin-4-oxo)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 432.2 P-0137

(R)-4-Chloro-5-(3-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrrolidine-1 -base) click

-3(2H)-one 401.1 99 P-0138

(R)-4-Chloro-5-(3-((2-(3,5-dimethyliso

oxazol-4-yl)pyridin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 388.2 P-0139

(R)-4-Chloro-5-(3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-2-(3-hydroxypropyl)pyridine

-3(2H)-one 447.0 P-0140

4-Chloro-2-(2,3-dihydroxypropyl)-5-((R)-3-((6-(3,5-dimethylisopropyl)

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 463.0 P-0141

(R)-2-(2-Aminoethyl)-4-chloro-5-(3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 432.3 P-0142

4-Chloro-5-((3S,4S)-3-fluoro-4-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy yl)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 463.3 P-0143

(R)-4-Chloro-2-(2-hydroxyethyl)-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 444.95 P-0144

4-Chloro-5-((3S,4S)-3-fluoro-4-((6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy yl)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 463.95 99 P-0145

4-Chloro-5-((3S,4S)-3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)da

-3(2H)-one 451.0 P-0146

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

azol-4-yl)-5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 450.1 P-0147

4-Chloro-5-((3S,4S)-3-fluoro-4-((6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy base)pyrrolidin-1-yl)pyridine

-3(2H)-one 420.0 P-0148

4-Chloro-5-((3S,4S)-3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 407.0 P-0149

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

oxazol-4-yl)-5-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 406.0 P-0150

(R)-4-Chloro-5-(3-((4-(3-(methoxymethyl)-5-methyliso

oxazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 418.0 P-0151

(R)-4-Chloro-5-(3-((6-fluoro-4-(5-methyl-1-((3-methyloxetan-3-yl)methyl)-1H -Pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 475.9 P-0152

(R)-4-Chloro-5-(3-((4-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-6-fluoropyridine -2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 459.0 P-0153

(R)-4-Chloro-5-(3-((4-(2,3-dimethyl-1H-indol-1-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 454.0 P-0154

(R)-4-Chloro-5-(3-((6-fluoro-4-(1-((3-fluoroazetidin-3-yl)methyl)-3,5-dimethyl -1H-Pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 492.0 P-0155

(R)-4-Chloro-5-(3-((4-(4-Chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyrrolidine-1- base)

-3(2H)-one 407.0 P-0156

(R)-4-Chloro-5-(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)da

-3-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 402.0 P-0157

(R)-4-Chloro-5-(3-((6-(1,3,5-trimethyl-1H-pyrazol-4-yl)da

-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 402.0 P-0158

(R)-4-Chloro-5-(3-((5-(3,5-dimethyliso

oxazol-4-yl)da

-3-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 389.0 P-0159

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4- yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 502.0 P-0160

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(2-

olinylethyl)-1H-pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 517.95 P-0161

(R)-4-Chloro-5-(3-((4-(1-(2-(dimethylamino)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl) -6-Fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 476.0 P-0162

(R)-4-Chloro-5-(3-((5-(3,5-dimethyliso

oxazol-4-yl)pyridin-3-yl)oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 388.0 P-0163

5,5'-((3R,3'R)-(pyridine-3,5-diylbis(oxy))bis(pyrrolidine-3,1-diyl))bis(4-chloropyridine

-3(2H)-keto) 506.0 P-0164

(R)-5-(3-((4-(3,5-Dimethyl-1-propyl-1H-pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrole pyridin-1-yl)da

-3(2H)-one 413.1 P-0165

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-propyl-1H-pyrazol-4-yl)-6-fluoropyridin-2-yl) oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 447.0 P-0166

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl) -6-Fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 500.95 P-0167

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl) -6-Fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 487.0 P-0168

(R)-4-Chloro-5-(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)pyrrolidine-1 -base) click

-3(2H)-one 401.0 P-0169

(R)-4-Chloro-5-(3-((4-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-6 -Fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 469.0 P-0170

(R)-4-Chloro-5-(3-((4-(1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl) oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 437.0 P-0171

(R)-4-Chloro-5-(3-((5-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one 419.0 P-0172

(R)-4-Chloro-5-(3-((4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoropyridin-2-yl ) oxy) pyrrolidin-1-yl) pyridine

-3(2H)-one 406.1 P-0173

(R)-4-Chloro-5-(3-((6-fluoro-4-(1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl )despair

-3(2H)-one 391.1 P-0174

(R)-4-Chloro-5-(3-((4-(2,4-dimethylthiazol-5-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl )despair

-3(2H)-one 422.0 P-0175

(R)-4-Chloro-5-(3-((4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 405.1 P-0176

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 432.4 P-0177

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 450.2 P-0178

(R)-4-Chloro-5-(3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 433.0 P-0179

4-Chloro-5-((3S,4S)-3-fluoro-4-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy base)pyrrolidin-1-yl)pyridine

-3(2H)-one 419.0 P-0180

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)pyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 406.0 P-0181

(R)-4-Chloro-5-(3-((6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidine-1 -base) click

-3(2H)-one 402.0 P-0182

R)-4-Chloro-5-(3-((6-(3,5-dimethyliso

oxazol-4-yl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 389.0 P-0183

(R)-4-Chloro-5-(3-((4-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-6-fluoropyridine-2 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 473.0 P-0184

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1H- Pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 489.3 P-0185

4-Chloro-5-((3R)-3-((4-(1-(3-Chloro-2-(hydroxymethyl)-2-methylpropyl)-3,5-dimethyl-1H -Pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 525.0 P-0186

(R)-4-Chloro-5-(3-((6-Fluoro-4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazole- 4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 477.0 P-0187

(R)-4-Chloro-5-(3-((4-(1-((3,3-difluorocyclobutyl)methyl)-3,5-dimethyl-1H-pyrazole-4 -yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)pyridine

-3(2H)-one 509.0 P-0188

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

azol-4-yl)-6-fluoropyridin-2-oxo)oxy)-4-fluoropyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 468.0 P-0189

4-Chloro-5-((3S,4S)-3-((4-(3,5-dimethyliso

oxazol-4-yl)-6-fluoropyridin-2-yl)oxy)-4-fluoropyrrolidin-1-yl)da

-3(2H)-one 424.0 P-0190

4-Chloro-5-((3S,4S)-3-fluoro-4-((6-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2 -yl)oxy)pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 481.3 P-0191

4-Chloro-5-((3S,4S)-3-fluoro-4-((6-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2 -yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 437.0 P-0192

(R)-4-Chloro-5-(3-((6-Fluoro-4-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine -2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 449.0 P-0193

(R)-4-Chloro-5-(3-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 405.0 P-0194

(R)-4-Chloro-5-(3-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidine -1-base) click

-3(2H)-one 405.0 P-0195

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

oxazol-4-yl)-6-fluoropyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 406.0 P-0196

(R)-4-Chloro-5-(3-(3-(1,5-dimethyl-1H-pyrazol-4-yl)phenoxy)pyrrolidin-1-yl)da

-3(2H)-one 386.0 P-0197

(R)-4-Chloro-5-(3-(3-(1,3-dimethyl-1H-pyrazol-4-yl)phenoxy)pyrrolidin-1-yl)da

-3(2H)-one 386.0 P-0198

(R)-4-Chloro-5-(3-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy)pyrrolidin-1-yl)da

-3(2H)-one 400.0 P-0199

(R)-4-Chloro-5-(3-((6-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)-2-(2-hydroxyethyl)pyridine

-3(2H)-one 463.9 P-0200

(R)-4-Chloro-5-(3-((6-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy) Pyrrolidin-1-yl)da

-3(2H)-one       P-0201

(R)-4-Chloro-5-(3-((4-(3,5-dimethyliso

oxazol-4-yl)pyridin-2-yl)pyrrolidin-1-yl)pyridine

-3(2H)-one 388.0 P-0202

(R)-3-Chloro-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-ethylbenzenesulfonamide 509.9 P-0203

(R)-4-Chloro-5-(3-((4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidine-1 -base) click

-3(2H)-one 401.1 P-0204

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)propane-1-sulfonamide 508.0 P-0205

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)isobutylamide 472.0 P-0206

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)cyclopentanecarboxamide 498.0 P-0207

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropyl-3,5-difluorobenzenesulfonamide 523.9 P-0208

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3,5-difluoro-N-propylbenzenesulfonamide 526.0 P-0209

(R)-4-Chloro-5-(3-((4-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl )despair

-3(2H)-one 387.1 P-0210

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-tolyl)cyclopropanesulfonamide. 502.0 P-0211

(R)-1-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)-3-cyclopropylurea 485.0 P-0212

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)cyclobutanamide 484.0 P-0213

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)acetamide 444.0 P-0214

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)benzamide 506.0 P-0215

5,5'-((3R,3'R)-([4,4'-bipyridine]-2,2'-diylbis(oxy))bis(pyrrolidine-3,1-diyl) ) Bis(4-Chloro)

-3(2H)-keto) 583.0 P-0216

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)-6-fluoropyridin-4-yl)-3-methyl-N-propylbenzenesulfonamide 522.0 P-0217

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)-6-fluoropyridin-4-yl)-N-cyclopropyl-3-methylbenzenesulfonamide 522.0 P-0218

(R)-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)acetate methyl ester 459.0 P-0219

(R)-2-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluorophenyl)acetic acid 444.95 P-0220

(R)-5-(3-((4-(4-Amino-2-fluorophenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 402.1 P-0221

R)-N-(1-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)piperidin-4-yl)cyclopropanesulfonamide 495.0 P-0222

(R)-N-(1-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)piperidin-4-yl)cyclopropanecarboxamide 459.0 P-0223

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-propylbenzenesulfonamide 490.0 P-0224

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropyl-3-fluoro-5-methylbenzenesulfonamide 520.0 P-0225

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-fluoro-5-methyl-N-propylbenzenesulfonamide 522.0 P-0226

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-propylpiperin

-1-Sulfonamide 498.0 P-0227

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropyl-3-methoxybenzenesulfonamide 518.0 P-0228

(R)-4-Chloro-5-(3-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)oxy )pyrrolidin-1-yl)pyridine

-3(2H)-one 431.1 P-0229

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylpiperidine

-1-Sulfonamide 496.0 P-0230

(R)-3-Chloro-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylbenzenesulfonamide 521.9 P-0231

(R)-4-Chloro-5-(3-((6-(trifluoromethyl)-[3,4'-dipyridin]-2'-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 437.95 P-0232

(R)-4-Chloro-5-(3-((4-(2-Chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 470.9 P-0233

(R)-3-Chloro-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-propylbenzenesulfonamide 523.9 P-0234

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropyl-3-fluorobenzenesulfonamide 506.0 P-0235

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropyl-3-methylbenzenesulfonamide 502.0 P-0236

(R)-4-Chloro-5-(3-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 437.0 P-0237

(R)-4-Chloro-5-(3-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 453.0 P-0238

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)-5-fluoropyridin-4-yl)-N-cyclopropylbenzenesulfonamide 505.9 P-0239

(R)-4-Chloro-5-(3-((4-(4-(propylsulfonyl)piperidine)

-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)da

-3(2H)-one 483.1 P-0240

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-3-methyl-N-propylbenzenesulfonamide 504.0 P-0241

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-(4-fluorophenyl)benzenesulfonamide 541.9 P-0242

(R)-N-Butyl-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)benzenesulfonamide 504.0 P-0243

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-ethylbenzenesulfonamide 475.9 P-0244

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-methylbenzenesulfonamide 462.0 P-0245

(R)-N-(4-(2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)phenyl)cyclopropanesulfonamide 488.0 P-0246

(R)-4-Chloro-5-(3-((4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)pyrrolidin-1-yl)da

-3(2H)-one 502.0 P-0247

(R)-4-(2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylbenzenesulfonamide 487.9 P-0248

(R)-4-Chloro-5-(3-((5-Chloro-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 535.9 P-0249

(R)-4-Chloro-5-(3-((5-Chloro-4-(4-(piperidin-1-ylsulfonyl)phenyl)pyridin-2-yl)oxy)pyrrolidine- 1-base) click

-3(2H)-one 549.9 P-0250

(R)-3-(5-Chloro-2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylbenzenesulfonamide 345.0 P-0251

(R)-4-(5-Chloro-2-((1-(5-Chloro-6-oxy-1,6-dihydrogen)

-4-yl)pyrrolidin-3-yl)oxy)pyridin-4-yl)-N-cyclopropylbenzenesulfonamide 521.9 P-0252

(R)-5-(3-((4-(1H-pyrrol-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-4-chloroda

-3(2H)-one 358.0 P-0253

(R)-2-((1-(5-Chloro-6-oxy-1,6-dihydropyridine

-4-yl)pyrrolidin-3-yl)oxy)-6-(pyrrolidin-1-yl)isonicotinonitrile 387.0 biological test method

使用以下分析法測試本發明之化合物：CD73 酶分析 Compounds of the invention were tested using the following assays: CD73 enzymatic assay

使用來自普洛麥格（Promega）之CellTiter-Glo®系統在基於螢光素酶之間接分析中量測CD73酶活性。藉由AMP（CD73之主要底物）抑制在ATP存在下之螢光素酶反應。將CD73酶添加至反應物使AMP轉化成腺苷，且釋放抑制，產生發光信號。CD73之抑制引起此發光信號之降低。CD73 enzymatic activity was measured in a luciferase-based indirect assay using the CellTiter-Glo® system from Promega. The luciferase reaction in the presence of ATP is inhibited by AMP, the major substrate of CD73. Addition of the CD73 enzyme to the reaction converts AMP to adenosine and releases the inhibition, resulting in a luminescent signal. Inhibition of CD73 resulted in a decrease in this luminescent signal.

在大腸桿菌中純化具有N端His標籤之人類CD73（胺基酸殘基27-549）。所有分析組分在具有0.01% Tween-20之50 mM HEPE緩衝液（pH 7.4）中製備。使用0.4 nM CD73及150 µM AMP進行CD73酶分析。9.5 µL CD73蛋白及9.5 µL AMP添加至含有1 µL不同濃度之測試化合物或DMSO媒劑之384孔盤的孔中，且在室溫下培育1小時。含有CD73、AMP及5% DMSO之16個孔充當高對照。16個含有AMP及5% DMSO之孔充當低對照。停止酶促反應，且藉由添加5 µL CellTiter-Glo® 2.0試劑及5 µL ATP（最終濃度為1 µM）間接量測AMP位準。在室溫下培育盤30分鐘之後，在帝肯板讀取器（Tecan plate reader）上讀取發光信號。計算個別濃度下之抑制相對於高及低對照之百分比。藉由使用非線性回歸來分析資料以產生IC₅₀ 值。測定基於細胞之分析中針對 CD73 之抑制劑活性 Human CD73 with an N-terminal His tag (amino acid residues 27-549) was purified in E. coli. All assay components were prepared in 50 mM HEPE buffer (pH 7.4) with 0.01% Tween-20. CD73 enzymatic assay was performed using 0.4 nM CD73 and 150 µM AMP. 9.5 µL of CD73 protein and 9.5 µL of AMP were added to wells of 384-well plates containing 1 µL of various concentrations of test compound or DMSO vehicle and incubated for 1 hour at room temperature. 16 wells containing CD73, AMP and 5% DMSO served as high controls. 16 wells containing AMP and 5% DMSO served as low controls. The enzymatic reaction was stopped and AMP levels were measured indirectly by adding 5 µL of CellTiter-Glo® 2.0 Reagent and 5 µL of ATP (1 µM final concentration). After incubating the plate for 30 minutes at room temperature, the luminescence signal was read on a Tecan plate reader. Percent inhibition relative to high and low controls at individual concentrations was calculated. Data were analyzed by using nonlinear regression to generate _IC50 values. Determination of inhibitor activity against CD73 in cell-based assays

表現CD73之CHO-K1細胞殖株係在CMV啟動子控制下穩定轉染表現人類CD73之質體後產生。在37℃下在供應有5% CO2的加濕培育箱中，在補充有10%胎牛血清及1 mg/ml G418之Ham's F-12K（Kaighn's）培養基中選擇細胞。如下進行分析。細胞以1×10⁴ 個/孔之密度接種於50 µL培養基中之96孔盤中。將最大濃度為5 mM之化合物在DMSO中以1:3連續稀釋，總計8點滴定。將各稀釋點之2 μL等分試樣添加至248 μL培養基中且向各孔中添加25 μL，在最大濃度點處提供10 µM化合物。將AMP稀釋於培養基中，且將25 µL添加至各孔，其中最終濃度為150 µM。4個含有0.2%經DMSO處理之細胞及AMP之孔充當高對照，且4個僅含有0.2% DMSO及AMP之培養基的孔充當低對照。在培育4小時之後，將20 µL上清液轉移至384孔盤。藉由添加5 µL CellTiter-Glo® 2.0試劑及5 µL之最終濃度為1 µM之ATP間接量測上清液中的AMP位準。在室溫下培育盤30分鐘之後，在帝肯板讀取器上讀取發光信號。計算個別濃度下之抑制相對於高及低對照之百分比。藉由使用非線性回歸來分析資料以產生IC₅₀ 值。A CHO-K1 cell clone expressing CD73 was generated after stable transfection of plastids expressing human CD73 under the control of the CMV promoter. Cells were selected in Ham's F-12K (Kaighn's) medium supplemented with 10% fetal bovine serum and 1 mg/ml G418 at 37°C in a humidified incubator supplied with 5% CO2. The analysis is performed as follows. Cells were seeded at a density of ¹ x 104/well in 96-well dishes in 50 µL of medium. Compounds at a maximum concentration of 5 mM were serially diluted 1:3 in DMSO for a total of 8 point titrations. A 2 μL aliquot of each dilution point was added to 248 μL of medium and 25 μL to each well, providing 10 μM compound at the point of maximum concentration. AMP was diluted in medium and 25 µL was added to each well to a final concentration of 150 µM. Four wells containing 0.2% DMSO-treated cells and AMP served as high controls, and four wells containing only 0.2% DMSO and AMP medium served as low controls. After 4 hours of incubation, 20 µL of the supernatant was transferred to a 384-well plate. AMP levels in the supernatant were measured indirectly by adding 5 µL of CellTiter-Glo® 2.0 Reagent and 5 µL of ATP at a final concentration of 1 µM. After incubating the plate for 30 minutes at room temperature, the luminescence signal was read on a Tecan plate reader. Percent inhibition relative to high and low controls at individual concentrations was calculated. Data were analyzed by using nonlinear regression to generate _IC50 values.

下表2提供指示如本文中在表1中所描述之例示性化合物之生物化學及/或細胞抑制活性之資料。在下表2中，提供如下活性：+++=0.001 µM ＜ IC₅₀ ＜10 µM；++=10 µM ＜ IC₅₀ ＜ 100 µM，+=100 µM ＜ IC₅₀ ＜ 1000 µM。表 2 P# CD73 IC₅₀ （ µM ） CHO-K1 CELL_VARIANT ： CD73 IC₅₀ （ uM ） P-0001 +++ +++ P-0002 +++ +++ P-0003 +++ +++ P-0004 +++ +++ P-0005 +++ +++ P-0006 +++ +++ P-0007 +++ +++ P-0008 +++ +++ P-0009 +++ +++ P-0010 +++ +++ P-0011 +++ +++ P-0012 +++ +++ P-0013 +++ +++ P-0014 +++ +++ P-0015 +++ +++ P-0016 +++ +++ P-0017 +++ +++ P-0018 +++ +++ P-0020 +++ +++ P-0021 +++ +++ P-0022 +++ +++ P-0023 +++ +++ P-0024 +++ +++ P-0025 +++ +++ P-0026 +++ +++ P-0027 +++ +++ P-0028 +++ +++ P-0029 +++ ++ P-0030 +++ +++ P-0031 +++ +++ P-0032 +++ +++ P-0033 +++ +++ P-0034 +++ +++ P-0035 +++ +++ P-0036 +++ +++ P-0037 +++ +++ P-0038 +++ +++ P-0039 +++ +++ P-0040 +++ +++ P-0041 +++ +++ P-0042 +++ +++ P-0043 +++ +++ P-0044 +++ +++ P-0045 +++ +++ P-0046 +++ +++ P-0047 +++ +++ P-0048 +++ +++ P-0049 +++ +++ P-0050 +++ +++ P-0051 +++ +++ P-0052 +++ ++ P-0053 +++ +++ P-0054 +++ +++ P-0055 +++ +++ P-0056 +++ +++ P-0057 +++ +++ P-0058 +++ +++ P-0059 +++ +++ P-0060 +++ +++ P-0061 +++ +++ P-0062 +++ +++ P-0063 +++ +++ P-0064 +++ +++ P-0065 +++ +++ P-0066 +++ +++ P-0067 +++ +++ P-0068 +++ +++ P-0069 +++ +++ P-0070 +++ +++ P-0071 +++ +++ P-0072 +++ +++ P-0073 +++ +++ P-0074 +++ +++ P-0075 +++ +++ P-0076 +++ +++ P-0077 +++ +++ P-0078 +++ +++ P-0079 +++ +++ P-0080 +++ ++ P-0081 +++ +++ P-0082 +++ +++ P-0083 +++ +++ P-0084 +++ +++ P-0085 +++ +++ P-0086 +++ +++ P-0087 +++ +++ P-0088 +++ +++ P-0089 +++ +++ P-0090 +++ +++ P-0091 +++ +++ P-0092 +++ +++ P-0093 +++ +++ P-0094 +++ +++ P-0095 +++ +++ P-0096 +++ +++ P-0097 +++ +++ P-0099 +++ +++ P-0100 +++ +++ P-0101 +++ ++ P-0102 +++ +++ P-0103 +++ ++ P-0104 +++ ++ P-0105 +++ +++ P-0106 +++ +++ P-0107 +++ ++ P-0108 +++ +++ P-0109 +++ +++ P-0110- +++ +++ P-0111 +++ ++ P-0112 +++ +++ P-0113 +++ +++ P-0114 +++ +++ P-0115 +++ +++ P-0116 +++ +++ P-0117 +++ +++ P-0118 +++ +++ P-0119 +++ +++ P-0120 +++ +++ P-0121 +++ +++ P-0122 +++ +++ P-0123 +++ +++ P-0124 +++ +++ P-0125 +++ +++ P-0126 +++ +++ P-0127 +++ +++ P-0128 +++ +++ P-0129 +++ +++ P-0130 +++ +++ P-0131 +++ +++ P-0132 +++ +++ P-0133 +++ +++ P-0134 +++ +++ P-0135 +++ +++ P-0136 +++ +++ P-0137 +++ +++ P-0138 +++ +++ P-0139 +++ +++ P-0140 +++ +++ P-0141 +++ +++ P-0142 +++ +++ P-0143 +++ +++ P-0144 +++ +++ P-0145 +++ +++ P-0146 +++ +++ P-0147 +++ +++ P-0148 +++ +++ P-0149 +++ +++ P-0150 +++ +++ P-0151 +++ +++ P-0152 +++ +++ P-0153 +++ +++ P-0154 +++ +++ P-0155 +++ +++ P-0156 +++ +++ P-0157 +++ +++ P-0158 +++ +++ P-0159 +++ +++ P-0160 +++ +++ P-0161 +++ +++ P-0162 +++ +++ P-0163 +++ +++ P-0164 +++ +++ P-0165 +++ +++ P-0166 +++ +++ P-0167 +++ +++ P-0168 +++ +++ P-0169 +++ +++ P-0170 +++ +++ P-0171 +++ +++ P-0172 +++ +++ P-0173 +++ +++ P-0174 +++ +++ P-0175 +++ +++ P-0176 +++ +++ P-0177 +++ +++ P-0178 +++ +++ P-0179 +++ +++ P-0180 +++ +++ P-0181 +++ +++ P-0182 +++ +++ P-0183 +++ +++ P-0184 +++ +++ P-0185 +++ +++ P-0186 +++ +++ P-0187 +++ +++ P-0188 +++ +++ P-0189 +++ +++ P-0190 +++ +++ P-0191 +++ +++ P-0192 +++ +++ P-0193 +++ +++ P-0194 +++ +++ P-0195 +++ +++ P-0196 +++ +++ P-0197 +++ +++ P-0198 +++ +++ P-0199 +++ +++ P-0200 +++ +++ P-0201 +++ +++ P-0202 +++ +++ P-0203 +++ +++ P-0204 +++ +++ P-0205 +++ +++ P-0206 +++ +++ P-0207 +++ +++ P-0208 +++ +++ P-0209 +++ +++ P-0210 +++ +++ P-0211 +++ +++ P-0212 +++ +++ P-0213 +++ +++ P-0214 +++ +++ P-0215 +++ ++ P-0216 +++ +++ P-0217 +++ +++ P-0218 +++ +++ P-0219 +++ ++ P-0220 +++ +++ P-0221 +++ +++ P-0222 +++ +++ P-0223 +++ +++ P-0224 +++ +++ P-0225 +++ +++ P-0226 +++ +++ P-0227 +++ +++ P-0228 +++ +++ P-0229 +++ +++ P-0230 +++ +++ P-0231 +++ +++ P-0232 +++ +++ P-0233 +++ +++ P-0234 +++ +++ P-0235 +++ +++ P-0236 +++ +++ P-0237 +++ +++ P-0238 +++ +++ P-0239 +++ +++ P-0240 +++ +++ P-0241 +++ +++ P-0242 +++ +++ P-0243 +++ +++ P-0244 +++ +++ P-0245 +++ +++ P-0246 +++ +++ P-0247 +++ +++ P-0248 +++ +++ P-0249 +++ +++ P-0250 +++ +++ P-0251 +++ +++ P-0252 +++ +++ P-0253 +++ ++ Table 2 below provides data indicative of the biochemical and/or cytostatic activity of exemplary compounds as described in Table 1 herein. In Table 2 below, the following activities are provided: +++=0.001 µM < _IC50 < 10 µM; ++=10 µM < _IC50 < 100 µM, +=100 µM < _IC50 < 1000 µM. Table 2 P# CD73IC50 ( µM ) _{_} CHO-K1 CELL_VARIANT : CD73 IC ₅₀ ( uM ) P-0001 +++ +++ P-0002 +++ +++ P-0003 +++ +++ P-0004 +++ +++ P-0005 +++ +++ P-0006 +++ +++ P-0007 +++ +++ P-0008 +++ +++ P-0009 +++ +++ P-0010 +++ +++ P-0011 +++ +++ P-0012 +++ +++ P-0013 +++ +++ P-0014 +++ +++ P-0015 +++ +++ P-0016 +++ +++ P-0017 +++ +++ P-0018 +++ +++ P-0020 +++ +++ P-0021 +++ +++ P-0022 +++ +++ P-0023 +++ +++ P-0024 +++ +++ P-0025 +++ +++ P-0026 +++ +++ P-0027 +++ +++ P-0028 +++ +++ P-0029 +++ ++ P-0030 +++ +++ P-0031 +++ +++ P-0032 +++ +++ P-0033 +++ +++ P-0034 +++ +++ P-0035 +++ +++ P-0036 +++ +++ P-0037 +++ +++ P-0038 +++ +++ P-0039 +++ +++ P-0040 +++ +++ P-0041 +++ +++ P-0042 +++ +++ P-0043 +++ +++ P-0044 +++ +++ P-0045 +++ +++ P-0046 +++ +++ P-0047 +++ +++ P-0048 +++ +++ P-0049 +++ +++ P-0050 +++ +++ P-0051 +++ +++ P-0052 +++ ++ P-0053 +++ +++ P-0054 +++ +++ P-0055 +++ +++ P-0056 +++ +++ P-0057 +++ +++ P-0058 +++ +++ P-0059 +++ +++ P-0060 +++ +++ P-0061 +++ +++ P-0062 +++ +++ P-0063 +++ +++ P-0064 +++ +++ P-0065 +++ +++ P-0066 +++ +++ P-0067 +++ +++ P-0068 +++ +++ P-0069 +++ +++ P-0070 +++ +++ P-0071 +++ +++ P-0072 +++ +++ P-0073 +++ +++ P-0074 +++ +++ P-0075 +++ +++ P-0076 +++ +++ P-0077 +++ +++ P-0078 +++ +++ P-0079 +++ +++ P-0080 +++ ++ P-0081 +++ +++ P-0082 +++ +++ P-0083 +++ +++ P-0084 +++ +++ P-0085 +++ +++ P-0086 +++ +++ P-0087 +++ +++ P-0088 +++ +++ P-0089 +++ +++ P-0090 +++ +++ P-0091 +++ +++ P-0092 +++ +++ P-0093 +++ +++ P-0094 +++ +++ P-0095 +++ +++ P-0096 +++ +++ P-0097 +++ +++ P-0099 +++ +++ P-0100 +++ +++ P-0101 +++ ++ P-0102 +++ +++ P-0103 +++ ++ P-0104 +++ ++ P-0105 +++ +++ P-0106 +++ +++ P-0107 +++ ++ P-0108 +++ +++ P-0109 +++ +++ P-0110- +++ +++ P-0111 +++ ++ P-0112 +++ +++ P-0113 +++ +++ P-0114 +++ +++ P-0115 +++ +++ P-0116 +++ +++ P-0117 +++ +++ P-0118 +++ +++ P-0119 +++ +++ P-0120 +++ +++ P-0121 +++ +++ P-0122 +++ +++ P-0123 +++ +++ P-0124 +++ +++ P-0125 +++ +++ P-0126 +++ +++ P-0127 +++ +++ P-0128 +++ +++ P-0129 +++ +++ P-0130 +++ +++ P-0131 +++ +++ P-0132 +++ +++ P-0133 +++ +++ P-0134 +++ +++ P-0135 +++ +++ P-0136 +++ +++ P-0137 +++ +++ P-0138 +++ +++ P-0139 +++ +++ P-0140 +++ +++ P-0141 +++ +++ P-0142 +++ +++ P-0143 +++ +++ P-0144 +++ +++ P-0145 +++ +++ P-0146 +++ +++ P-0147 +++ +++ P-0148 +++ +++ P-0149 +++ +++ P-0150 +++ +++ P-0151 +++ +++ P-0152 +++ +++ P-0153 +++ +++ P-0154 +++ +++ P-0155 +++ +++ P-0156 +++ +++ P-0157 +++ +++ P-0158 +++ +++ P-0159 +++ +++ P-0160 +++ +++ P-0161 +++ +++ P-0162 +++ +++ P-0163 +++ +++ P-0164 +++ +++ P-0165 +++ +++ P-0166 +++ +++ P-0167 +++ +++ P-0168 +++ +++ P-0169 +++ +++ P-0170 +++ +++ P-0171 +++ +++ P-0172 +++ +++ P-0173 +++ +++ P-0174 +++ +++ P-0175 +++ +++ P-0176 +++ +++ P-0177 +++ +++ P-0178 +++ +++ P-0179 +++ +++ P-0180 +++ +++ P-0181 +++ +++ P-0182 +++ +++ P-0183 +++ +++ P-0184 +++ +++ P-0185 +++ +++ P-0186 +++ +++ P-0187 +++ +++ P-0188 +++ +++ P-0189 +++ +++ P-0190 +++ +++ P-0191 +++ +++ P-0192 +++ +++ P-0193 +++ +++ P-0194 +++ +++ P-0195 +++ +++ P-0196 +++ +++ P-0197 +++ +++ P-0198 +++ +++ P-0199 +++ +++ P-0200 +++ +++ P-0201 +++ +++ P-0202 +++ +++ P-0203 +++ +++ P-0204 +++ +++ P-0205 +++ +++ P-0206 +++ +++ P-0207 +++ +++ P-0208 +++ +++ P-0209 +++ +++ P-0210 +++ +++ P-0211 +++ +++ P-0212 +++ +++ P-0213 +++ +++ P-0214 +++ +++ P-0215 +++ ++ P-0216 +++ +++ P-0217 +++ +++ P-0218 +++ +++ P-0219 +++ ++ P-0220 +++ +++ P-0221 +++ +++ P-0222 +++ +++ P-0223 +++ +++ P-0224 +++ +++ P-0225 +++ +++ P-0226 +++ +++ P-0227 +++ +++ P-0228 +++ +++ P-0229 +++ +++ P-0230 +++ +++ P-0231 +++ +++ P-0232 +++ +++ P-0233 +++ +++ P-0234 +++ +++ P-0235 +++ +++ P-0236 +++ +++ P-0237 +++ +++ P-0238 +++ +++ P-0239 +++ +++ P-0240 +++ +++ P-0241 +++ +++ P-0242 +++ +++ P-0243 +++ +++ P-0244 +++ +++ P-0245 +++ +++ P-0246 +++ +++ P-0247 +++ +++ P-0248 +++ +++ P-0249 +++ +++ P-0250 +++ +++ P-0251 +++ +++ P-0252 +++ +++ P-0253 +++ ++

本文中所引用之所有專利及其他參考文獻指示熟習本發明所涉及之技術者的技能水準，且以全文引用之方式以相同程度併入，包括任何表及圖，如同各參考文獻個別地以全文引用之方式併入本文中一般。All patents and other references cited herein indicate the level of skill of those skilled in the art to which this invention pertains, and are incorporated by reference in their entirety to the same extent, including any tables and figures, as if each reference were individually set forth in their entirety The manner of reference is incorporated herein generally.

熟習此項技術者將易於瞭解，本發明完全適合於獲得所提及之目的及優點以及其中固有之目的及優點。本文所描述之方法、變化、組合物及實施例為例示性的且不欲限制本發明之範疇。熟習此項技術者將想到涵蓋在本發明之精神內的其中之變化及其他用途。Those skilled in the art will readily appreciate that the present invention is well suited to attain the objects and advantages mentioned as well as those inherent therein. The methods, variations, compositions, and examples described herein are illustrative and not intended to limit the scope of the invention. Variations therein and other uses encompassed within the spirit of the invention will occur to those skilled in the art.

對熟習此項技術者而言將容易顯而易見的係，可在不背離本發明之範疇及精神的情況下對本文中所描述之發明內容進行不同的取代及修改。舉例而言，可以進行變化以提供本發明之化合物之其他化合物及/或可使用各種投與方法。因此，此類其他實施例屬於本發明之範疇及以下申請專利範圍內。It will be readily apparent to those skilled in the art that various substitutions and modifications of the invention described herein can be made without departing from the scope and spirit of the invention. For example, changes can be made to provide other compounds of the compounds of the invention and/or various methods of administration can be used. Accordingly, such other embodiments are within the scope of the present invention and the scope of the following claims.

本文中說明性地所描述之本發明可在不存在本文中未特定揭示之任何元件、多個元件、限制或多個限制之情況下適合地實踐。已採用之術語及表達用作描述而非限制之術語，且在使用此類術語及表達中不意欲排除所展示及描述之特徵的任何等效物或其部分，但應認識到，在本發明所主張之範疇內，各種修改係可能的。因此，應瞭解，儘管本發明已由實施例及視情況選用之特徵特定地描述，但熟習此項技術者可採取本文所描述之概念的修改及變化形式，且此類修改及變化形式應視為屬於隨附申請專利範圍所界定之本發明之範疇。The invention illustratively described herein may suitably be practiced in the absence of any element, elements, limitation or limitations not specifically disclosed herein. The terms and expressions have been employed as terms of description rather than limitation, and the use of such terms and expressions is not intended to exclude any equivalents or parts of the features shown and described, but it is recognized that in the present invention Various modifications are possible within the claimed scope. Therefore, it should be understood that although the invention has been specifically described by the embodiments and optional features, modifications and variations of the concepts described herein may be employed by those skilled in the art, and such modifications and variations should be considered It is within the scope of the present invention as defined by the scope of the appended claims.

此外，若本發明之特徵或態樣關於替代方案之群組描述，則熟習此項技術者將認識到本發明亦籍此關於本文中所描述之群組之任何個別成員或成員之子組描述。Furthermore, if a feature or aspect of the invention is described with respect to groups of alternatives, those skilled in the art will recognize that the invention is also described herewith with respect to any individual member or subgroup of members of the group described herein.

此外，除非相反地指示，否則若提供各種數值以用於實施例，則其他實施例藉由採用任何2個不同值作為範圍之端點描述。此類範圍亦屬於本發明之範疇內。Furthermore, where various numerical values are provided for an embodiment, other embodiments are described by employing any 2 different values as the endpoints of the range, unless indicated to the contrary. Such ranges are also within the scope of the present invention.

因此，其他實施例屬於本發明之範疇及以下申請專利範圍內。Therefore, other embodiments fall within the scope of the present invention and the scope of the following claims.

無without

無without

Claims (47)

一種具有式I之化合物：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中：A 係5-6員芳族環或4-7員含氮雜環烷基，其中A經0-3個R⁴ 取代，其限制條件為當環A為4-7員含氮雜環烷基時，則式I之嗒

酮部分連接至A之氮原子；E 係苯基或5或6員雜芳基，其中E經0-3個Q及0-1個R¹¹ 取代，其限制條件為當E為5或6員雜芳基時，O不連接至E之雜原子；L 不存在，為-C(O)N(H)-、C₀ -C₃ 伸烷基、-N(H)-或-O-；G 為以下基團中之一者： (a)   經0-4個T¹ 及0-1個T² 取代之環烷基； (b)   經0-4個T¹ 及0-1個T² 取代之環烯基； (c)   經0-4個T¹ 及0-1個T² 取代之橋接碳環； (d)   碳環螺環，其含有兩個藉由一個共同螺碳原子連接之環烷基，其中該碳環螺環係經0-4個T¹ 及0-1個T² 取代； (e)   含有兩個具有至少一個雜原子之環狀基團之雜環螺環，其中該兩個環狀基團由一個共同螺碳原子連接，其中該雜環螺環經0-3個T⁵ 、0-1個T⁶ 取代； (f)   經0-4個T¹ 及0-1個T⁴ 取代之苯基； (g)   經0-4個T⁵ 及0-1個T⁶ 取代之雜環烷基； (h)   經0-4個T⁵ 及0-1個T⁶ 取代之雜環烯基； (i)    經0-4個T⁵ 及0-1個T⁶ 取代之橋接雜環；或 (j)    經0-3個T⁵ 及0-1個T³ 取代之雜芳基； 各Q 獨立地為鹵素、CN或視情況經1-3個鹵素取代之烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之烷基、視情況經1-3個R^b 取代之烯基、視情況經1-3個R^b 取代之炔基、CN、氰烷基、視情況經1-3個R^b 取代之烷氧基或視情況經1-3個R^b 取代之烷氧基烷基；T² 係-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -C(O)R¹⁰ 、-(CH₂ )_0-3 -C(O)H、-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ 、視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基；T³ 係-(CH₂ )_0-3 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -環烷基、-(CH₂ )_0-3 -環烯基、-(CH₂ )_0-3 -雜環烷基、-(CH₂ )_0-3 -雜環烯基、視情況經4-氯嗒

-3-酮-5-基取代之-O-雜環烷基，或-(CH₂ )_0-3 -橋接碳環，其中-(CH₂ )_0-3 -環烷基、-(CH₂ )_0-3 -環烯基、-(CH₂ )_0-3 -雜環烷基、-(CH₂ )_0-3 -雜環烯基，或-(CH₂ )_0-3 -橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不可以連接至T³ 之氧原子或氮原子；T⁴ 係-(CH₂ )_0-3 C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ ，或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之烷基、視情況經1-3個R^b 取代之烯基、視情況經1-3個R^b 取代之炔基、CN、氰烷基、視情況經1-3個R^b 取代之烷氧基，或視情況經1-3個R^b 取代之烷氧基烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之烷氧基；T⁶ 係-(CH₂ )_0-3 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ -R⁷ 、-(CH₂ )_0-3 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-3 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-3 -N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-3 -C(O)OR⁹ 、-(CH₂ )_0-3 -C(O)R¹⁰ 、-(CH₂ )_0-3 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-3 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氧原子或氮原子；R^a 為H或烷基；R^b 為鹵素、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ；R¹ 為H、烷氧基烷基、經0-4個Z² 取代之烯基或經0-4個Z² 取代之C₂ -C₆ 烷基；R² 為H、鹵素、烷基、烯基、烷氧基、鹵烷基、CF₃ 或CN；R³ 為H、鹵素、烷基、CN或鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之烷基；R⁷ 係視情況經1-4個Z⁴ 取代之烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基；R⁸ 係H、視情況經1-4個Z⁴ 取代之烷基、視情況經1-4個Z⁴ 取代之烯基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基、視情況1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基，或經0-5個T¹ 取代之橋接碳環； 各R⁹ 獨立地為H或視情況經1-4個Z⁴ 取代之烷基；R¹⁰ 係經0-4個Z⁴ 取代之烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-環烷基、視情況經1-4個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₃ 烷基-雜環烷基；R¹¹ 為NH₂ ；Z¹ 為氰烷基、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為C(O)OR⁹ ； 各Z² 獨立地為羥基、鹵素、NH₂ 或CN，其限制條件為不超過1個Z² 可以為NH₂ ； 各Z³ 獨立地為烷基、鹵素、鹵烷基、羥基、羥烷基、烷氧基、烷氧基烷基或CN； 各Z⁴ 獨立地為羥基、鹵素、烷氧基或CN；且 各Z⁵ 獨立地為烷基、鹵烷基、羥基、羥烷基、鹵素、烷氧基、烷氧基烷基、CN或氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、烷氧基或CN。A compound of formula I:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein: A is a 5-6 membered aromatic ring or a 4-7 membered nitrogen-containing heterocycloalkane group, wherein ^A is substituted with 0-3 R4, with the limitation that when ring A is a 4-7 membered nitrogen-containing heterocycloalkyl, then the formula I

The ketone moiety is attached to the nitrogen atom of A; E is phenyl or 5- or ⁶ -membered heteroaryl, wherein E is substituted with 0-3 Q and 0-1 R, with the proviso that when E is 5- or 6-membered In the case of heteroaryl, O is not attached to the heteroatom of E; L is absent and is -C(O)N(H)-, Co _{- C3alkylene} , -N(H)- or -O-; G is one of the following groups: (a) cycloalkyl substituted with 0-4 T ¹ and 0-1 T ² ; (b) 0-4 T ¹ and 0-1 T ² substituted cycloalkenyl; (c) bridged carbocycles substituted with 0-4 T ¹ and 0-1 T ² ; (d) carbocyclic spiro rings, which contain two spiro rings connected by a common spiro carbon atom Cycloalkyl, wherein the carbocyclic spiro ring system is substituted with 0-4 T ¹ and 0-1 T ² ; (e) Heterocyclic spiro rings containing two cyclic groups with at least one heteroatom, wherein The two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring is substituted by 0-3 T ⁵ , 0-1 T ⁶ ; (f) by 0-4 T ¹ and 0- 1 T ⁴ substituted phenyl; (g) 0-4 T ⁵ and 0-1 T ⁶ substituted heterocycloalkyl; (h) 0-4 T ⁵ and 0-1 T ⁶ Substituted heterocycloalkenyl; (i) bridged heterocycle substituted with 0-4 T ⁵ and 0-1 T ⁶ ; or (j) substituted with 0-3 T ⁵ and 0-1 T ³ Heteroaryl; each Q is independently halogen, CN, or alkyl optionally substituted with 1-3 halogens; each ^T1 is independently halogen, hydroxy, alkyl optionally substituted with 1-3 ^Rb , Alkenyl optionally substituted with 1-3 R ^b , alkynyl optionally substituted with 1-3 R ^b , CN, cyanoalkyl, alkoxy optionally substituted with 1-3 R ^b or optionally Case alkoxyalkyl substituted with 1-3 R ^b ; T ² is -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ) ₂ ) _0-3 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _{0 -3} -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)N(R ⁸ ) R ⁹ , -(CH ₂ ) _0-3 -C(O)OR ⁹ , -(CH ₂ ) _0-3 -C(O)R ¹⁰ , -(CH ₂ ) _0-3 -C(O)H, -(C H ₂ ) _0-3 -N(R ⁹ )C(O)R ¹⁰ , optionally -(CH ₂ ) _0-3 cycloalkyl substituted by 1-4 Z ³ , optionally by 1-3 Z ⁵ -substituted -(CH ₂ ) _0-3 -phenyl, or -(CH ₂ ) _0-3 heteroaryl substituted by 1-3 Z ⁵ as appropriate; T ³ is -(CH ₂ ) _0-3 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)OR ⁹ , -(CH ₂ ) _0-3 -cycloalkyl, -( _CH2 ) _0-3 -cycloalkenyl, -( _CH2 ) _0-3 -heterocycloalkyl, -( _CH2 ) _0-3 -heterocycloalkenyl, 4-Chloropyridine

-O-heterocycloalkyl substituted with -3-keto-5-yl, or -(CH ₂ ) _0-3 -bridged carbocycle, wherein -(CH ₂ ) _0-3 -cycloalkyl, -(CH ₂ ) _0-3 -cycloalkenyl, -( _CH2 ) _0-3 -heterocycloalkyl, -( _CH2 ) _0-3 -heterocycloalkenyl, or -( _CH2 ) _0-3 -bridged carbocycle Each is optionally substituted with 1-3 Z ⁵ and 0-1 Z ¹ , with the limitation that when T ³ is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of T ³ ; T ⁴ System -(CH ₂ ) _0-3 C(O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 - N(R ⁹ )C(O)N(R ⁸ )R ⁹ , or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, alkyl optionally substituted with 1-3 R ^b , optionally Alkenyl optionally substituted with 1-3 R ^b , alkynyl optionally substituted with 1-3 R ^b , CN, cyanoalkyl, alkoxy optionally substituted with 1-3 R ^b , or optionally substituted with 1-3 R b Case alkoxyalkyl substituted with 1-3 R ^b , with the proviso that when T ⁵ is attached to a heteroatom of G, T ⁵ cannot be halogen, hydroxy, CN or optionally 1-3 R ^b Substituted alkoxy; T ⁶ is -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-3 -SO ₂ -R ⁷ , -(CH ₂ ) _{0 -3} -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-3 -N(R ⁹ )C( O)OR ⁹ , -(CH ₂ ) _0-3 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-3 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _{0 -3} -C(O)OR ⁹ , -(CH ₂ ) _0-3 -C(O)R ¹⁰ , -(CH ₂ ) _0-3 -N(R ⁹ )C(O)R ¹⁰ , -N( H)C(H)C=O, optionally substituted with 1-4 Z ³ -(CH ₂ ) _0-3 cycloalkyl, optionally substituted with 1-4 Z ³ -(CH ₂ ) _{0 -2} Heterocycloalkyl, as the case may be Substituted with 1-3 Z ⁵ -(CH ₂ ) _0-3 heteroaryl, or 4-chloroda

-3-keto-5-yl, with the restriction that when ^T6 is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of ^T6 ; R ^a is H or an alkyl group; R ^b is a halogen , CN, CF ₃ or hydroxyl, with the limitation that no more than 1 R ^b can be CF ₃ ; R ¹ is H, alkoxyalkyl, alkenyl substituted by 0-4 Z ² or 0-4 C ₂ -C ₆ alkyl substituted with Z ² ; R ² is H, halogen, alkyl, alkenyl, alkoxy, haloalkyl, CF ₃ or CN; R ³ is H, halogen, alkyl, CN or haloalkyl; each R ⁴ is independently halogen, CN or alkyl optionally substituted with 1-3 halogens; R ⁷ is optionally alkyl substituted with 1-4 Z ⁴ , optionally 1- 4 Z ³ substituted -C ₀ -C ₃ alkyl-cycloalkyl, optionally 1-4 Z ³ substituted -C ₀ -C ₃ alkyl-phenyl, optionally 1-3 Z substituted ⁵ -substituted -C ₀ -C ₃ alkyl-heteroaryl, or -C ₀ -C ₃ alkyl-heterocycloalkyl substituted by 1-3 Z ⁵ as appropriate; R ⁸ is H, optionally substituted by 1-4 Z ⁴ substituted alkyl, optionally 1-4 Z ⁴ substituted alkenyl, optionally 1-4 Z ³ substituted -C ₀ -C ₃ alkyl-cycloalkyl, optionally -C ₀ -C ₃ alkyl-phenyl substituted by 1-4 Z ³ in the case, -C ₀ -C ₃ alkyl-heteroaryl substituted by 1-3 Z ⁵ in the case, and 1- -C ₀ -C ₃ alkyl-heterocycloalkyl substituted with 3 Z ⁵ , or bridged carbocycle substituted with 0-5 T ¹ ; each R ⁹ is independently H or optionally through 1-4 Z ⁴ -substituted alkyl; R ¹⁰ is alkyl substituted with 0-4 Z ⁴ , optionally -C ₀ -C ₃ alkyl-cycloalkyl substituted with 1-4 Z ³ , optionally 1- 4 Z ³ substituted -C ₀ -C ₃ alkyl-phenyl, optionally 1-3 Z ⁵ substituted -C ₀ -C ₃ alkyl-heteroaryl, or optionally 1-3 Z 5 substituted -C 0 -C 3 alkyl-heteroaryl -C ₀ -C ₃ alkyl-heterocycloalkyl substituted by Z ⁵ ; R ¹¹ is NH ₂ ; Z ¹ is cyanoalkyl, -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , with the restriction that when Z ¹ is attached to a heteroatom, then Z ¹ is not C(O)OR ⁹ ; each Z ² is independently Hydroxyl, halogen, NH ₂ or CN, with the limitation that no more than one Z ² can be NH ₂ ; each Z ³ is independently alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkane Oxyalkyl or CN; each ^Z is independently hydroxy, halo, alkoxy, or CN; and each ^Z is independently alkyl, haloalkyl, hydroxy, hydroxyalkyl, halo, alkoxy, alkane ^Oxyalkyl , CN or cyanoalkyl, with the proviso that when Z is attached to a heteroatom, then Z ⁵ is not halogen, hydroxy, alkoxy or CN. 如請求項1之化合物，其中環A為吖呾、吡咯啶、哌啶、咪唑、噻唑或吡唑基。The compound of claim 1, wherein ring A is acridine, pyrrolidine, piperidine, imidazole, thiazole or pyrazolyl. 如請求項1之化合物，其具有式II：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中L 不存在，為-N(H)-或-O-；且m 為0-2。The compound of claim 1 having formula II:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein L is absent, -N(H)- or -O-; and m is 0 -2. 如請求項1之化合物，其具有式IIIa或IIIb：

或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，其中：E 為苯基或6員雜芳基，其中E經0-2個Q取代，其限制條件為當E為6員雜芳基時，O不連接至E之雜原子；G 為以下基團中之一者： (k)    經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (l)     經0-3個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (m)   經0-3個T¹ 及0-1個T² 取代之5-9員橋接碳環； (n)    5-9員碳環螺環，其含有兩個由一個共同螺碳原子連接之環烷基，其中該碳環螺環係經0-3個T¹ 及0-1個T² 取代； (o)    6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-3個T⁵ 、0-1個T⁶ 取代； (p)    經0-3個T¹ 及0-1個T⁴ 取代之苯基； (q)    經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基； (r)     經0-3個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基； (s)     經0-3個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (t)     經0-3個T⁵ 及0-1個T³ 取代之5-6員雜芳基； 各Q獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₃ 烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₆ 烷基、視情況經1-3個R^b 取代之C₂ -C₅ 烯基、視情況經1-3個R^b 取代之C₂ -C₅ 炔基、CN、C₁ -C₆ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基C₁ -C₆ 烷基；T² 係-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)R¹⁰ 、-(CH₂ )_0-2 -C(O)H、-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ 、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-2 -5-6員雜芳基；T³ 係-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基、視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基，或-(CH₂ )_0-2 -5-9員橋接碳環，其中該-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基或-(CH₂ )_0-2 -5-9員橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不可以連接至T³ 之氧原子或氮原子；T⁴ 係-(CH₂ )_0-2 C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₆ 烷基、視情況經1-3個R^b 取代之C₂ -C₆ 烯基、視情況經1-3個R^b 取代之C₂ -C₆ 炔基、CN、C₁ -C₆ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基C₁ -C₆ 烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之C₁ -C₆ 烷氧基；T⁶ 係-(CH₂ )_0-2 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ -R⁷ 、-(CH₂ )_0-2 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-2 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)R¹⁰ 、-(CH₂ )_0-2 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-2 -5-6員雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-3 -5-6員雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氧原子或氮原子；R^a 係H或C₁ -C₆ 烷基；R^b 為鹵素、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ；R¹ 為氫、C₁ -C₆ 烷氧基C₁ -C₆ 烷基、經1-4個Z² 取代之C₂ -C₆ 烯基或經1-4個Z² 取代之C₂ -C₆ 烷基；R² 為H、鹵素、C₁ -C₆ 烷基、C₂ -C₆ 烯基、C₁ -C₆ 烷氧基、C₁ -C₆ 鹵烷基、CF₃ 或CN；R³ 為H、鹵素、C₁ -C₆ 烷基、CN或C₁ -C₆ 鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₃ 烷基； R⁷ 為視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基，視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基；R⁸ 係H、視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z⁴ 取代之C₂ -C₆ 烯基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基，或經0-4個T¹ 取代之5-9員橋接碳環； 各R⁹ 獨立地為H或視情況經1-4個Z⁴ 取代之C₁ -C₆ 烷基；R¹⁰ 係經0-4個Z⁴ 取代之C₁ -C₆ 烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-C₀ -C₂ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₂ 烷基-5-6員雜環烷基；R¹¹ 為NH₂ ；Z¹ 為C₁ -C₆ 氰烷基、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為-C(O)OR⁹ ； 各Z² 獨立地為羥基、鹵素、CN； 各Z³ 獨立地為C₁ -C₆ 烷基、鹵素、C₁ -C₆ 鹵烷基、羥基、C₁ -C₆ 羥烷基、C₁ -C₆ 烷氧基或CN； 各Z⁴ 獨立地為羥基、鹵素、C₁ -C₆ 烷氧基或CN；且 各Z⁵ 獨立地為C₁ -C₆ 烷基、C₁ -C₆ 鹵烷基、羥基、C₁ -C₆ 羥烷基、鹵素、C₁ -C₆ 烷氧基、CN或C₁ -C₆ 氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、C₁ -C₆ 烷氧基或CN。The compound of claim 1 having formula Ilia or IIIb:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein: E is phenyl or 6-membered heteroaryl, wherein E is through 0-2 Q Substituted with the proviso that when E is a 6-membered heteroaryl, O is not attached to a heteroatom of E; G is one of the following groups: (k) via 0-3 T and ^0-1 C ₃ -C ₆ cycloalkyl substituted with T ² ; (l) C 3 -C 6 cycloalkenyl substituted with 0-3 T ¹ and 0-1 T ² ; (m) C ₃ -C ₆ cycloalkenyl substituted with 0-3 T s ¹ and 0-1 T substituted 5-9 membered bridged carbocycles; (n) 5-9 membered carbocyclic spiro rings containing ^two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic ring The spiro ring system is substituted with 0-3 T ¹ and 0-1 T ² ; (o) 6-9 membered heterocyclic spiro rings, which contain two cyclic groups with at least one heteroatom, wherein the two The cyclic group is connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted with 0-3 T ⁵ , 0-1 T ⁶ ; (p) through 0-3 T ¹ and 0-1 phenyl substituted with T ⁴ ; (q) 4-6 membered heterocycloalkyl substituted with 0-3 T ⁵ and 0-1 T ⁶ ; (r) 0-3 T ⁵ and 0-1 4-6 membered heterocycloalkenyl substituted with T ⁶ ; (s) 5-9 membered bridged heterocycle substituted with 0-3 T ⁵ and 0-1 T ⁶ ; or (t) 0-3 membered heterocycle 5-6 membered heteroaryl substituted with T ⁵ and 0-1 T ³ ; each Q is independently halogen, CN or C ₁ -C ₃ alkyl substituted with 1-3 halogen as the case may be; each T ¹ is independently is halogen, hydroxy, optionally C ₁ -C ₆ alkyl substituted with 1-3 R ^b , optionally C ₂ -C ₅ alkenyl substituted with 1-3 R ^b , optionally 1-3 C ₂ -C ₅ alkynyl substituted with 1 R ^b , CN, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ alkoxy substituted with 1-3 R ^b as appropriate, or optionally 1-C 6 alkoxy substituted with 1-3 R b C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted with 3 R ^b ; T ² is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ N(R ⁸ ) R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)R ¹⁰ , - (CH ₂ ) _0-2 -C(O)H, -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ , -(CH ₂ ) optionally substituted by 1-4 Z ³ ) _0-2 C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-2 -phenyl substituted with 1-3 Z ⁵ , or -( optionally substituted with 1-3 Z ⁵ ) CH ₂ ) _0-2-5-6 membered heteroaryl; T ³ is -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N( R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-2 -5 -6-membered heterocycloalkyl, optionally via 4-chloropyridine

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl, or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycle, wherein -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-2 -5-6 membered heterocycloalkyl or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycles each optionally via 1- 3 Z ⁵ and 0-1 Z ¹ substitutions, with the limitation that when T ³ is connected to the heteroatom of G, G cannot be connected to the oxygen atom or nitrogen atom of T ³ ; T ⁴ is -(CH ₂ ) _0-2 C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C (O)N(R ⁸ )R ⁹ or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, C ₁ -C ₆ alkyl optionally substituted with 1-3 R ^b , optionally 1-3 R ^b substituted C ₂ -C ₆ alkenyl, optionally 1-3 R ^b substituted C ₂ -C ₆ alkynyl, CN, C ₁ -C ₆ cyanoalkyl, optionally 1 -C ₁ -C ₆ alkoxy substituted with 3 R ^b , or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted with 1-3 R ^b as the case may be, with the limitation that when T When ⁵ is attached to the heteroatom of G, T ⁵ cannot be halogen, hydroxyl, CN or C ₁ -C ₆ alkoxy substituted by 1-3 R ^b as the case may be; T ⁶ is -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ -R ⁷ , -(CH ₂ ) _0-2 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _{0- 2} -C(O)R ¹⁰ , -(CH ₂ ) _0-2 -N(R ⁹ )C(O)R ¹⁰ , -N(H)C(H)C=O, 1-4 as the case may be Z ³ replaces - (CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-2-5-6 membered heterocycloalkyl substituted with 1-4 Z ³ , optionally with 1 -3 Z ⁵ substituted -(CH ₂ ) _0-3 -5-6-membered heteroaryl, or 4-chloroda

-3-keto- ⁵ -yl, with the limitation that when T is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of T _; ^R is H or C ₁ -C ⁶ alkyl ; R ^b is halogen, CN, CF ₃ or hydroxyl, with the limitation that no more than one R ^b can be CF ₃ ; R ¹ is hydrogen, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, via 1-4 Z ² substituted C ₂ -C ₆ alkenyl or 1-4 Z ² substituted C ₂ -C ₆ alkyl; R ² is H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, CF ₃ or CN; R ³ is H, halogen, C ₁ -C ₆ alkyl, CN or C ₁ -C ₆ haloalkyl; each R ⁴ is independently halogen, CN or C ₁ -C ₃ alkyl optionally substituted with 1-3 halogens; R ⁷ is C ₁ - optionally substituted with 1-4 Z ⁴ C ₆ alkyl, optionally -C ₀ -C ₂ alkyl-C ₃ -C ₆ cycloalkyl substituted with 1-4 Z ³ , optionally -C ₀ -C substituted with 1-4 Z ³ ₂ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heteroaryl, or optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heterocycloalkyl; R ⁸ is H, optionally C ₁ -C ₆ alkyl substituted with 1-4 Z ⁴ , optionally substituted with 1-4 Z ⁴ C ₂ -C ₆ alkenyl, optionally -C ₀ -C ₂ alkyl-C ₃ -C ₆ cycloalkyl substituted with 1-4 Z ³ , optionally -C substituted with 1-4 Z ³ ₀ -C ₂ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₂ alkyl-5-6 membered heteroaryl, optionally substituted with 1-3 Z ⁵ - C ₀ -C ₂ alkyl-5-6 membered heterocycloalkyl, or a 5-9 membered bridged carbocycle substituted with 0-4 T ¹ ; each R ⁹ is independently H or optionally through 1-4 Z ⁴ substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl substituted with 0-4 Z ⁴ , optionally -C ₀ -C ₂ alkane substituted with 1-4 Z ³ base-C ₃ -C ₆ cycloalkyl, optionally -C ₀ -C ₂ alkyl-phenyl substituted with 1-4 Z ³ , -C ₀ -C optionally substituted with 1-3 Z ⁵ ₂ -alkyl-5-6-membered heteroaryl, or -C ₀ -C ₂ -alkyl-5-6-membered heterocycloalkyl substituted by 1-3 Z ⁵ as appropriate; R ¹¹ is NH ₂ ; Z ¹ is C ₁ -C ₆ cyanoalkyl, -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C(O)-N(R ⁸ )R ⁹ , which limits condition is when Z ¹ is connected to the atom, then Z ¹ is not -C(O)OR ⁹ ; each Z ² is independently hydroxyl, halogen, CN; each Z ³ is independently C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ halogen alkyl, hydroxy, _{C1 -} C6hydroxyalkyl, _{C1 -} C6alkoxy, or CN; each ^Z4 is independently hydroxy, halogen, _{C1 -} C6alkoxy, or CN; and each ^Z5 independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, C ₁ -C ₆ hydroxyalkyl, halogen, C ₁ -C ₆ alkoxy, CN or C ₁ -C ₆ cyano Alkyl, with the proviso that when Z ⁵ is attached to a heteroatom, then Z ⁵ is not halogen, hydroxy, C ₁ -C ₆ alkoxy, or CN. 如前述請求項中任一項之化合物，其中：E 為苯基或6員雜芳基，其中E經0-1個Q取代，其限制條件為當E為6員雜芳基時，O不連接至E之雜原子；G 為以下基團中之一者： (a)   經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (b)   經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (c)   經0-2個T¹ 及0-1個T² 取代之5-9員橋接碳環； (d)   5-9員碳環螺環，其含有兩個由一個共同螺碳原子連接之環烷基，其中該碳環螺環係經0-2個T¹ 及0-1個T² 取代； (e)   6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代； (f)   經0-2個T¹ 及0-1個T⁴ 取代之苯基； (g)   經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烷基； (h)   經0-2個T⁵ 及0-1個T⁶ 取代之4-6員雜環烯基； (i)    經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (j)    經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基；Q 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₄ 烷基； 各T¹ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₄ 烷基、視情況經1-3個R^b 取代之C₂ -C₄ 烯基、視情況經1-3個R^b 取代之C₂ -C₄ 炔基、CN、C₁ -C₄ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基C₁ -C₄ 烷基；T² 係-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)R¹⁰ 、-(CH₂ )_0-1 -C(O)H、-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 、視情況經1-3個Z³ 取代之-(CH₂ )_0-2 C₃ -C₆ 環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -苯基，或視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基；T³ 係-(CH₂ )_0-2 -C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-2 -N(R⁸ )R⁹ 、-(CH₂ )_0-2 -C(O)OR⁹ 、-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-2 -5-6員雜環烷基、視情況經4-氯嗒

-3-酮-5-基取代之-O-5-6員雜環烷基，或-(CH₂ )_0-2 -5-9員橋接碳環，其中該-(CH₂ )_0-2 -C₃ -C₆ 環烷基、-(CH₂ )_0-1 -5-6員雜環烷基或-(CH₂ )_0-2 -5-9員橋接碳環各自視情況經1-3個Z⁵ 及0-1個Z¹ 取代，其限制條件為當T³ 連接至G之雜原子時，G不可以連接至T³ 之氧原子或氮原子；T⁴ 係-(CH₂ )_0-1 C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ ，或N(R^a )₂ ； 各T⁵ 獨立地為鹵素、羥基、視情況經1-3個R^b 取代之C₁ -C₄ 烷基、視情況經1-3個R^b 取代之C₂ -C₄ 烯基、視情況經1-3個R^b 取代之C₂ -C₄ 炔基、CN、C₁ -C₆ 氰烷基、視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基，或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基C₁ -C₄ 烷基，其限制條件為當T⁵ 連接至G之雜原子時，T⁵ 不可以為鹵素、羥基、CN或視情況經1-3個R^b 取代之C₁ -C₄ 烷氧基；T⁶ 係-(CH₂ )_0-1 -N(R⁹ )SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ -R⁷ 、-(CH₂ )_0-1 -SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )SO₂ N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)N(R⁸ )R⁹ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R⁸ 、-(CH₂ )_0-1 -N(R⁹ )C(O)OR⁹ 、-(CH₂ )_0-1 -N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ 、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)R¹⁰ 、-(CH₂ )_0-1 -N(R⁹ )C(O)R¹⁰ 、-N(H)C(H)C=O、視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -C₃ -C₆ 環烷基、視情況經1-4個Z³ 取代之-(CH₂ )_0-1 -5-6員雜環烷基、視情況經1-3個Z⁵ 取代之-(CH₂ )_0-1 -5-6員雜芳基，或4-氯嗒

-3-酮-5-基，其限制條件為當T⁶ 連接至G之雜原子時，G不可以連接至T⁶ 之氧原子或氮原子；R^a 為H或C₁ -C₄ 烷基；R^b 為F、Cl、CN、CF₃ 或羥基，其限制條件為不超過1個R^b 可以為CF₃ ；R¹ 為氫、C₁ -C₄ 烷氧基C₁ -C₄ 烷基、經1-3個Z² 取代之C₂ -C₄ 烯基或經1-3個Z² 取代之C₂ -C₄ 烷基；R² 為H、鹵素、C₁ -C₄ 烷基、C₂ -C₄ 烯基、C₁ -C₄ 烷氧基、C₁ -C₄ 鹵烷基、CF₃ 或CN；R³ 為H、鹵素、C₁ -C₄ 烷基、CN或C₁ -C₄ 鹵烷基； 各R⁴ 獨立地為鹵素、CN或視情況經1-3個鹵素取代之C₁ -C₄ 烷基；R⁷ 為視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z³ 取代之-C₀ -C₃ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₃ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基；R⁸ 為H、視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z⁴ 取代之C₂ -C₄ 烯基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基，或經0-3個T¹ 取代之5-9員橋接碳環； 各R⁹ 獨立地為H或視情況經1-3個Z⁴ 取代之C₁ -C₄ 烷基；R¹⁰ 為視情況經0-3個Z⁴ 取代之C₁ -C₄ 烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-C₃ -C₆ 環烷基、視情況經1-3個Z³ 取代之-C₀ -C₁ 烷基-苯基、視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜芳基，或視情況經1-3個Z⁵ 取代之-C₀ -C₁ 烷基-5-6員雜環烷基；Z¹ 為C₁ -C₄ 氰烷基、-(CH₂ )_0-1 -C(O)OR⁹ 、-(CH₂ )_0-1 -C(O)-N(R⁸ )R⁹ ，其限制條件為當Z¹ 連接至雜原子時，則Z¹ 不為-C(O)OR⁹ ； 各Z² 獨立地為羥基、鹵素或CN； 各Z³ 獨立地為C₁ -C₄ 烷基、鹵素、C₁ -C₄ 鹵烷基、羥基、C₁ -C₄ 羥烷基、C₁ -C₄ 烷氧基或CN； 各Z⁴ 獨立地為羥基、鹵素、C₁ -C₄ 烷氧基或CN；且 各Z⁵ 獨立地為C₁ -C₄ 烷基、C₁ -C₆ 鹵烷基、羥基、C₁ -C₄ 羥烷基、鹵素、C₁ -C₄ 烷氧基、CN或C₁ -C₄ 氰烷基，其限制條件為當Z⁵ 連接至雜原子時，則Z⁵ 不為鹵素、羥基、C₁ -C₄ 烷氧基或CN。The compound of any one of the preceding claims, wherein: E is phenyl or 6-membered heteroaryl, wherein E is substituted with 0-1 Q, with the proviso that when E is 6-membered heteroaryl, O is not A heteroatom attached to E; G is one of the following groups: (a) C ₃ -C ₆ cycloalkyl substituted with 0-2 T ¹ and 0-1 T ² ; (b) through 0 -C ₃ -C ₆ cycloalkenyl substituted with 2 T ¹ and 0-1 T ² ; (c) 5-9 membered bridged carbocycle substituted with 0-2 T ¹ and 0-1 T ² ; (d) 5-9 membered carbocyclic spiro rings containing two cycloalkyl groups connected by a common spiro carbon atom, wherein the carbocyclic spiro rings are substituted with 0-2 T ¹ and 0-1 T ² (e) a 6-9 membered heterocyclic spiro ring containing two cyclic groups with at least one heteroatom, wherein the two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro Ring system substituted with 0-2 T ⁵ , 0-1 T ⁶ ; (f) phenyl substituted with 0-2 T ¹ and 0-1 T ⁴ ; (g) 0-2 T ⁵ and 4-6-membered heterocycloalkyl substituted with 0-1 T ⁶ ; (h) 4-6-membered heterocycloalkenyl substituted with 0-2 T ⁵ and 0-1 T ⁶ ; (i) with 5-9 membered bridged heterocycle substituted with 0-2 T ⁵ and 0-1 T ⁶ ; or (j) 5-6 membered heteroaryl substituted with 0-2 T ⁵ and 0-1 T ³ Q is independently halogen, CN or _C1 - _C4 alkyl optionally substituted with 1-3 halogens; each ^T1 is independently halogen, hydroxy, C1 optionally substituted with _1-3 ^Rb -C ₄ alkyl, C ₂ -C ₄ alkenyl optionally substituted with 1-3 R ^b , C ₂ -C ₄ alkynyl optionally substituted with 1-3 R ^b , CN, C ₁ -C ₄ cyanoalkyl, optionally C ₁ -C ₄ alkoxy substituted with 1-3 R ^b , or C ₁ -C ₄ alkoxy C ₁ -C ₄ optionally substituted with 1-3 R ^b Alkyl; T ² is -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 - SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C( O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-1 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _0-1 -C(O)R ¹⁰ , -(CH ₂ ) _0-1 -C(O)H, -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ , optionally substituted with 1-3 Z ³ -(CH ₂ ) _0-2 C ₃ -C ₆ cycloalkyl, optionally substituted with 1-3 Z ⁵ Substituted -(CH ₂ ) _0-1 -phenyl, or -(CH ₂ ) _0-1 -5-6-membered heteroaryl substituted by 1-3 Z ⁵ as appropriate; T ³ is -(CH ₂ ) _0-2 -C(O)N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -N(R ⁸ )R ⁹ , -(CH ₂ ) _0-2 -C(O)OR ⁹ , -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-2 -5-6 membered heterocycloalkyl, optionally via 4-chlorocarbonate

-O-5-6 membered heterocycloalkyl substituted by -3-keto-5-yl, or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycle, wherein -(CH ₂ ) _0-2 -C ₃ -C ₆ cycloalkyl, -(CH ₂ ) _0-1 -5-6 membered heterocycloalkyl or -(CH ₂ ) _0-2 -5-9 membered bridged carbocycles each optionally via a 1- 3 Z ⁵ and 0-1 Z ¹ substitutions, with the limitation that when T ³ is connected to the heteroatom of G, G cannot be connected to the oxygen atom or nitrogen atom of T ³ ; T ⁴ is -(CH ₂ ) _0-1 C(O)OR ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C (O)N(R ⁸ )R ⁹ , or N(R ^a ) ₂ ; each T ⁵ is independently halogen, hydroxy, optionally C ₁ -C ₄ alkyl substituted with 1-3 R ^b , optionally C ₂ -C ₄ alkenyl substituted with 1-3 R ^b , C ₂ -C ₄ alkynyl optionally substituted with 1-3 R ^b , CN, C ₁ -C ₆ cyanoalkyl, optionally C ₁ -C ₄ alkoxy substituted with 1-3 R ^b , or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl substituted with 1-3 R ^b as the case may be, with the limitation that when When T ⁵ is attached to the heteroatom of G, T ⁵ cannot be halogen, hydroxy, CN or C ₁ -C ₄ alkoxy substituted by 1-3 R ^b as the case may be; T ⁶ is -(CH ₂ ) _{0- 1} -N(R ⁹ )SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ -R ⁷ , -(CH ₂ ) _0-1 -SO ₂ N(R ⁸ )R ⁹ , -(CH ) ₂ ) _0-1 -N(R ⁹ )SO ₂ N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)N(R ⁸ )R ⁹ , -(CH ) ₂ ) _0-1 -N(R ⁹ )C(O)R ⁸ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)OR ⁹ , -(CH ₂ ) _0-1 -N( R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)-N(R ⁸ )R ⁹ , -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _{0 -1} -C(O)R ¹⁰ , -(CH ₂ ) _0-1 -N(R ⁹ )C(O)R ¹⁰ , -N(H)C(H)C=O, 1-4 as appropriate Z ³ substitutions -(CH ₂ ) _0-1 -C ₃ -C ₆ cycloalkyl, optionally -(CH ₂ ) _0-1 -5-6 membered heterocycloalkyl substituted with 1-4 Z ³ , optionally Substituted by 1-3 Z ⁵ -(CH ₂ ) _0-1-5-6 -membered heteroaryl, or 4-chloroda

-3-keto-5-yl, with the restriction that when ^T6 is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of ^T6 ; R ^a is H or C ₁ -C ₄ alkyl ; R ^b is F, Cl, CN, CF ₃ or hydroxyl, with the limitation that no more than one R ^b can be CF ₃ ; R ¹ is hydrogen, C ₁ -C _4alkoxy C ₁ -C ₄ alkyl , C ₂ -C ₄ alkenyl substituted by 1-3 Z ² or C ₂ -C ₄ alkyl substituted by 1-3 Z ² ; R ² is H, halogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, CF ₃ or CN; R ³ is H, halogen, C ₁ -C ₄ alkyl, CN or C ₁ -C ₄ haloalkyl; each R ⁴ is independently halogen, CN or C ₁ -C ₄ alkyl optionally substituted with 1-3 halogens; R ⁷ is C optionally substituted with 1-3 Z ⁴ ₁ -C ₄ alkyl, optionally -C ₀ -C ₃ alkyl-C ₃ -C ₆ cycloalkyl substituted with 1-3 Z ³ , -C ₀ optionally substituted with 1-3 Z ³ -C ₃ alkyl-phenyl, optionally -C ₀ -C ₁ alkyl-5-6 membered heteroaryl substituted with 1-3 Z ⁵ as appropriate, or optionally substituted with 1-3 Z ⁵ - C ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl; R ⁸ is H, optionally C ₁ -C ₄ alkyl substituted with 1-3 Z ⁴ , optionally with 1-3 Z ⁴ Substituted C ₂ -C ₄ alkenyl, optionally substituted with 1-3 Z ³ -C ₀ -C ₁ alkyl-C ₃ -C ₆ cycloalkyl, optionally substituted with 1-3 Z ³ -C ₀ -C ₁ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₁ alkyl-5-6 membered heteroaryl, optionally substituted with 1-3 Z ⁵ -C ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl, or a 5-9 membered bridged carbocycle substituted with 0-3 T ¹ ; each R ⁹ is independently H or optionally through 1- 3 Z ⁴ substituted C ₁ -C ₄ alkyl; R ¹⁰ is optionally C ₁ -C ₄ alkyl substituted with 0-3 Z ⁴ , optionally -C ₀ substituted with 1-3 Z ³ -C ₁ alkyl-C ₃ -C ₆ cycloalkyl, optionally substituted with 1-3 Z ³ -C ₀ -C ₁ alkyl-phenyl, optionally substituted with 1-3 Z ⁵ - C ₀ -C ₁ alkyl-5-6 membered heteroaryl, or -C ₀ -C ₁ alkyl-5-6 membered heterocycloalkyl substituted with 1-3 Z ⁵ as appropriate; Z ¹ is C ₁ -C ₄ cyanoalkyl, -(CH ₂ ) _0-1 -C(O)OR ⁹ , -(CH ₂ ) _0-1 -C(O)-N(R ⁸ )R ⁹ , with the restriction that When Z ¹ is attached to a heteroatom, then Z ¹ is not -C(O)OR ⁹ ; each Z ² is independently hydroxy, halogen or CN; each Z ³ is independently C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ haloalkyl, hydroxy, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, or CN; each Z ⁴ is independently hydroxy, halogen, C ₁ -C ₄ alkoxy, or CN; and each Z ⁵ is independently C ₁ -C ₄ alkyl, C ₁ -C ₆ haloalkyl, hydroxy, C ₁ -C ₄ hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CN or C ₁ -C ₄ cyanoalkyl, limited thereto ^The proviso is that when Z5 is attached to a heteroatom, then Z5 is not halogen, hydroxy, _{C1 -} ^C4alkoxy , or CN. 如前述請求項中任一項之化合物，其中R¹ 為氫。A compound as claimed in any preceding claim, wherein R ¹ is hydrogen. 2、3、4或5中任一項之化合物，其中R¹ 為C₁ -C₄ 烷氧基C₁ -C₄ 烷基、經1-3個Z² 取代之C₂ -C₄ 烯基或經1-3個Z² 取代之C₂ -C₄ 烷基。The compound of any one of 2, 3, 4 or 5, wherein R ¹ is C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl substituted with 1-3 Z ² Or C ₂ -C ₄ alkyl substituted with 1-3 Z ² . 2、3、4或5中任一項之化合物，其中R¹ 係-CH₂ CH₂ OH、-CH₂ CH₂ CH₂ OH、-CH₂ CH(OH)CH₂ OH，或-CH₂ CH(CH₃ )OH；R² 為Cl、Br、CF₃ 或CN；且E 係吡啶基、苯基、嘧啶基或嗒

基。The compound of any one of ₂ , ₃ , ₄ , or ₅ , wherein ^R1 is _-CH2CH2OH , _-CH2CH2CH2OH , -CH2CH ₍ OH ₎ CH2OH, or -CH2CH (CH ₃ )OH; R ² is Cl, Br, CF ₃ or CN; and E is pyridyl, phenyl, pyrimidinyl or pyridyl

base. 如請求項8之化合物，其中R² 為Cl。The compound of claim 8, wherein R ² is Cl. 2、3、4或5中任一項之化合物，其中R¹ 係H；R² 係Cl、Br、CF₃ 或CN；R⁴ 係鹵素；且E 係吡啶基、苯基、嘧啶基或嗒

基。The compound of any one of 2, 3, 4, or 5, wherein ^R1 is H; ^R2 is Cl, Br, _CF3 , or CN; ^R4 is halogen; and E is pyridyl, phenyl, pyrimidinyl, or pyridyl

base. 如請求項10之化合物，其中R² 為Cl。The compound of claim 10, wherein R ² is Cl. 如請求項1至5中任一項之化合物，其具有下式中之任一者：

， 或其醫藥學上可接受之鹽，其中R² 係Cl、Br、CF₃ 或CN，且m 為0-1。The compound of any one of claims 1 to 5, which has any one of the following formulae:

, or a pharmaceutically acceptable salt thereof, wherein R ² is Cl, Br, CF ₃ or CN, and m is 0-1. 如請求項1至5中任一項之化合物，其具有下式中之任一者：

， 或其醫藥學上可接受之鹽，其中R² 為Cl、Br、CF₃ 或CN。The compound of any one of claims 1 to 5, which has any one of the following formulae:

, or a pharmaceutically acceptable salt thereof, wherein R ² is Cl, Br, CF ₃ or CN. 如請求項1至5中任一項之化合物，其具有下式中之任一者：

. 或其醫藥學上可接受之鹽，其中R² 為Cl、Br、CF₃ 或CN。The compound of any one of claims 1 to 5, which has any one of the following formulae:

. or a pharmaceutically acceptable salt thereof, wherein R ² is Cl, Br, CF ₃ or CN. 如請求項12之化合物，其具有式IV（a）、IV（b）、IV（c）、IV（d）、IV（e）、IV（f）中之一者或其醫藥學上可接受之鹽。The compound of claim 12, which has one of formula IV(a), IV(b), IV(c), IV(d), IV(e), IV(f) or is pharmaceutically acceptable of salt. 如請求項13之化合物，其具有式V（a）、V（b）、V（c）、V（d）、V（e）、V（f）、V（g）、V（h）、V（i）、V（j）、V（k）、V（l）、V（m）、V（n）、V（o）、V（p）、V（q）、V（r）、 V（s）、V（t）、V（u）、V（v）、V（w）、V（af）、V（ag）、V（ah）、V（ai）、V（aj）、V（ak）、V（al）、V（am）、V（an）、V（ao）、V（ap）、V（aq）、V（ar）、V（as）、V（at）、 V（au）、V（av）、V（aw）、V（ay）、V（az）、V（ba）、V（bb）中之一者或其醫藥學上可接受之鹽。The compound of claim 13 having formula V(a), V(b), V(c), V(d), V(e), V(f), V(g), V(h), V(i), V(j), V(k), V(l), V(m), V(n), V(o), V(p), V(q), V(r), V(s), V(t), V(u), V(v), V(w), V(af), V(ag), V(ah), V(ai), V(aj), V(ak), V(al), V(am), V(an), V(ao), V(ap), V(aq), V(ar), V(as), V(at), One of V(au), V(av), V(aw), V(ay), V(az), V(ba), V(bb) or a pharmaceutically acceptable salt thereof. 如請求項14之化合物，其具有式VI（a）、VI（b）、VI（c）、VI（d）、VI（e）、VI（f）、VI（g）、VI（h）、VI（i）、VI（j）、VI（k）、VI（l）、VI（m）、VI（n）、VI（o）中之一者或其醫藥學上可接受之鹽。The compound of claim 14 having formula VI(a), VI(b), VI(c), VI(d), VI(e), VI(f), VI(g), VI(h), One of VI(i), VI(j), VI(k), VI(l), VI(m), VI(n), VI(o) or a pharmaceutically acceptable salt thereof. 如前述請求項中任一項之化合物，其中G 為以下基團中之一者： (a) 經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烷基； (b) 經0-2個T¹ 及0-1個T² 取代之C₃ -C₆ 環烯基； (c) 6-9員雜環螺環，其含有兩個具有至少一個雜原子之環狀基團，其中該兩個環狀基團係由一個共同螺碳原子連接，其中該雜環螺環係經0-2個T⁵ 、0-1個T⁶ 取代； (d) 經0-2個T¹ 及0-1個T⁴ 取代之苯基； (e) 經0-2個T⁵ 及0-1個T⁶ 取代之5-6員雜環烷基； (f) 經0-2個T⁵ 及0-1個T⁶ 取代之5-6員雜環烯基； (g) 經0-2個T⁵ 及0-1個T⁶ 取代之5-9員橋接雜環；或 (h) 經0-2個T⁵ 及0-1個T³ 取代之5-6員雜芳基。The compound of any one of the preceding claims, wherein G is one of the following groups: (a) C ₃ -C ₆ cycloalkyl substituted with 0-2 T ¹ and 0-1 T ² ; (b) C ₃ -C ₆ cycloalkenyl substituted with 0-2 T ¹ and 0-1 T ² ; (c) 6-9 membered heterocyclic spiro rings containing two atoms having at least one heteroatom A cyclic group, wherein the two cyclic groups are connected by a common spiro carbon atom, wherein the heterocyclic spiro ring system is substituted by 0-2 T ⁵ , 0-1 T ⁶ ; (d) by 0 - phenyl substituted with 2 T ¹ and 0-1 T ⁴ ; (e) 5-6 membered heterocycloalkyl substituted with 0-2 T ⁵ and 0-1 T ⁶ ; (f) 0-1 T 6 substituted - 5-6 membered heterocycloalkenyl substituted with 2 T ⁵ and 0-1 T ⁶ ; (g) 5-9 membered bridged heterocycle substituted with 0-2 T ⁵ and 0-1 T ⁶ ; or (h) 5-6 membered heteroaryl substituted with 0-2 T ⁵ and 0-1 T ³ . 如請求項16之化合物，其中G係吡唑基、異

唑基、吲哚基、1,2,3-***基、咪唑基、噻唑基或吡咯基，其中之每一者經0-2個T⁵ 及0-1個T³ 取代。The compound of claim 16, wherein G is pyrazolyl, iso

azolyl, indolyl, 1,2,3-triazolyl, imidazolyl, thiazolyl or pyrrolyl, each ^of which is substituted with 0-2 ^T5 and 0-1 T3. 如請求項16之化合物，其中G係哌

基、哌啶、吡咯啶、四氫哌喃、

啉基、1,2,3,6-四氫吡啶基、2,5-二氫吡咯基或3,6-二氫哌喃基，其中之每一者係經0-2個T⁵ 及0-1個T⁶ 取代。The compound of claim 16, wherein G is piperidine

base, piperidine, pyrrolidine, tetrahydropyran,

olinyl, 1,2,3,6-tetrahydropyridyl, 2,5-dihydropyrrolyl or 3,6-dihydropyranyl, each of which is terminated by 0-2 T ⁵ and 0 - 1 T ⁶ substitution. 如請求項16之化合物，其中G為(1R,5S)-3,8-二氮雜二環[3.2.1]辛基、(1R,5S)-3-氮雜二環[3.2.1]辛基或(1R,5S)-8-氮雜二環[3.2.1]辛基，其中之每一者係經0-2個T⁵ 及0-1個T⁶ 取代。The compound of claim 16, wherein G is (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3-azabicyclo[3.2.1] Octyl or (1R,5S)-8 ^- azabicyclo[3.2.1]octyl, each of which is substituted with 0-2 T5 and 0-1 ^T6 . 如請求項16之化合物，其中G為環己基、環戊基、環己烯基、環戊烯基，其中之每一者係經0-2個T¹ 及0-1個T² 取代。The compound of claim 16, wherein G is cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, each of which is substituted with 0-2 T ¹ and 0-1 T ² . 如請求項1至3或6至17中任一項之化合物，其中T³ 為-CH₂ C(O)N(H)環丙基、-CH₂ C(O)N(H)CH₃ 、-CH₂ -COOH、氧雜環丁烷基、-(CH₂ )_0-2 環丙基、-(CH₂ )_0-2 環丁基、-(CH₂ )_0-2 -四氫哌喃、-(CH₂ )_0-2 -四氫呋喃、-(CH₂ )_0-2 吖呾基、-(CH₂ )_0-2 吡咯啶基，或-(CH₂ )_0-2

啉基。The compound of any one of claims 1 to 3 or 6 to 17, wherein T ³ is -CH ₂ C(O)N(H)cyclopropyl, -CH ₂ C(O)N(H)CH ₃ , -CH ₂ -COOH, oxetanyl, -(CH ₂ ) _0-2 cyclopropyl, -(CH ₂ ) _0-2 cyclobutyl, -(CH ₂ ) _0-2 -tetrahydropyran , -(CH ₂ ) _0-2 -tetrahydrofuran, -(CH ₂ ) _0-2 acryl, -(CH ₂ ) _0-2 pyrrolidinyl, or -(CH ₂ ) _0-2

Linyl. 如請求項1至17中任一項之化合物，其中G 為下式中之一者：

.The compound of any one of claims 1 to 17, wherein G is one of the following formulae:

. 如請求項1至17中任一項之化合物，其中G 為下式中之一者：

. 各T^1a 獨立地為F、Cl或CH₃ ；且 各T^5a 獨立地為F、Cl或CH₃ 。The compound of any one of claims 1 to 17, wherein G is one of the following formulae:

. each T ^1a is independently F, CI or CH ₃ ; and each T ^5a is independently F, CI or CH ₃ . 如請求項25之化合物，其中G 為式（a）、（b）、（c）、（d）、（e）、（f）、（g）或（h）中之一者。The compound of claim 25, wherein G is one of formula (a), (b), (c), (d), (e), (f), (g) or (h). 如請求項25之化合物，其中G 為式（i）、（j）、（k）、（l）、（m）、（n）、（o）、（p）、（q）、（r）、（s）、（t）、（u）、（v）、（w）、（x）、（y）、（z）、（aa）、（ab）、（ac）或（ad）中之一者。The compound of claim 25, wherein G is of formula (i), (j), (k), (l), (m), (n), (o), (p), (q), (r) , (s), (t), (u), (v), (w), (x), (y), (z), (aa), (ab), (ac) or (ad) one. 如請求項25之化合物，其中G 為式（ae）、（af）、（ag）、（ah）、（ai）、（aj）、（ak）、（al）、（am）、（an）、（ao）、（ap）或（aq）中之一者。The compound of claim 25, wherein G is of formula (ae), (af), (ag), (ah), (ai), (aj), (ak), (al), (am), (an) One of , (ao), (ap) or (aq). 如請求項25之化合物，其中G 為式（ar）或（as）中之一者。The compound of claim 25, wherein G is one of formula (ar) or (as). 如請求項25之化合物，其中G 為式（at）或（au）中之一者。The compound of claim 25, wherein G is one of formula (at) or (au). 如請求項25之化合物，其中G 為式（av）、（aw）、（ax）、（ay）或（az）中之一者。The compound of claim 25, wherein G is one of formula (av), (aw), (ax), (ay) or (az). 如請求項1至3、6至25或27中任一項之化合物，其中T⁶ 氧雜環丁烷基亞甲基、-C(O)CH₂ OH、-C(O)OH、-SO₂ CH₃ 、-C(O)環丙基、-C(O)CH₃ 、-N(H)SO₂ -環丙基、-N(H)C(O)環丙基、-SO₂ N(H)CH₂ CH₂ CH₃ 、-SO₂ NH環丙基或-SO₂ CH₂ CH₂ CH₃ 。The compound of any one of claims 1 to 3, 6 to 25 or 27, wherein T ⁶ oxetanylmethylene, -C(O)CH ₂ OH, -C(O)OH, -SO ₂ CH ₃ , -C(O)cyclopropyl, -C(O)CH ₃ , -N(H)SO ₂ -cyclopropyl, -N(H)C(O) cyclopropyl, -SO ₂ N _{( H ) CH2CH2CH3 , -SO2NHcyclopropyl or -SO2CH2CH2CH3} . 如請求項1至3、6至25、27或29中任一項之化合物，其中T⁵ 為F、Cl、CH₂ Cl、CH₂ F、CH₃ 、-CH₂ CH₃ 、-CH(CH₃ )₂ 、CH₂ OH、-CH₂ CH₂ OH、-CH₂ C(CH₃ )₂ OH、-CH(CH₂ OH)₂ 、-CH₂ CH(OH)CF₃ 、CH₂ CF₃ 、CN、-CH₂ CN、-OCH₃ 、-CH₂ OCH₃ 、-CHF₂ 、-CH₂ CHF₂ 、-CH₂ CH(OH)CH₂ CH₂ Cl、-CH(CH₂ OH)CH₂ Cl、-CH(CH₂ OH)CH₂ I或-CH₂ C(CH₃ )(CH₂ OH)CH₂ Cl。The compound of any one of claims 1 to 3, 6 to 25, 27 or 29, wherein T ⁵ is F, Cl, CH ₂ Cl, CH ₂ F, CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ C(CH ₃ ) ₂ OH, -CH(CH ₂ OH) ₂ , -CH ₂ CH(OH)CF ₃ , CH ₂ CF ₃ , CN, _-CH2CN , _-OCH3 , _-CH2OCH3 , _-CHF2 , _-CH2CHF2 , -CH2CH ₍ OH _{) CH2CH2Cl} , -CH _{( CH2OH ) CH2Cl} , -CH(CH2OH)CH2I or _-CH2C ( _{CH3 ) (} CH2OH _{) CH2Cl} . 如請求項1至25中任一項之化合物，其中Z⁵ 為CH₃ 、F、Cl、CN、-CH₂ CN、-CH₂ CH₃ 或OH。The compound of any one of claims 1 to 25, wherein Z ⁵ is CH ₃ , F, Cl, CN, -CH ₂ CN, -CH ₂ CH ₃ or OH. 如請求項1之化合物，其選自表1，或其醫藥學上可接受之鹽。The compound of claim 1, which is selected from Table 1, or a pharmaceutically acceptable salt thereof. 一種醫藥組合物，其包含如前述請求項中任一項之化合物及醫藥學上可接受之載劑。A pharmaceutical composition comprising a compound of any of the preceding claims and a pharmaceutically acceptable carrier. 如請求項36 之醫藥組合物，其進一步包含第二藥劑。The pharmaceutical composition of claim 36 , further comprising a second agent. 一種用於治療患有由CD73介導之疾病或病況之個體之方法，該方法包含向該個體投與有效量之如請求項1 至 35 中任一項之化合物或其醫藥學上可接受之鹽、溶劑合物、互變異構體、立體異構體或氘代類似物，或如請求項36 至 37 中任一項之醫藥組合物。A method for treating an individual suffering from a disease or condition mediated by CD73, the method comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 35 , or a pharmaceutically acceptable form thereof A salt, solvate, tautomer, stereoisomer or deuterated analog, or a pharmaceutical composition as in any one of claims 36 to 37 . 如請求項38 之用於治療疾病或病況之方法，其中該疾病或病況係贅生性病症、癌症、年齡相關之疾病、發炎性病症、認知病症及或神經退化性疾病。The method for treating a disease or condition of claim 38 , wherein the disease or condition is a neoplastic disorder, cancer, age-related disease, inflammatory disorder, cognitive disorder, and/or neurodegenerative disease. 如請求項38 之用於治療疾病或病況之方法，其中該疾病或病況係膀胱癌、大腸直腸癌、胃癌、膽囊癌、多形性神經膠質母細胞瘤、神經膠質瘤、白血病、淋巴瘤、肺癌、乳癌、黑色素瘤、多發性骨髓瘤、卵巢癌、***癌、胰腺癌、甲狀腺癌、肺纖維化、肝纖維化、阿茲海默氏病、多發性硬化症或帕金森氏病。The method for treating a disease or condition as claimed in claim 38 , wherein the disease or condition is bladder cancer, colorectal cancer, gastric cancer, gallbladder cancer, glioblastoma multiforme, glioma, leukemia, lymphoma, Lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, pulmonary fibrosis, liver fibrosis, Alzheimer's disease, multiple sclerosis or Parkinson's disease. 如請求項40 之用於治療疾病或病況之方法，其中該淋巴瘤係成人T細胞淋巴瘤、AIDS相關淋巴瘤、未分化大細胞淋巴瘤、血管免疫母細胞T細胞淋巴瘤、B細胞淋巴瘤、伯基特氏淋巴瘤（Burkitt's lymphoma）、皮膚T細胞淋巴瘤、彌漫性大B細胞淋巴瘤、腸病相關T細胞淋巴瘤、濾泡性淋巴瘤、肝脾T細胞淋巴瘤、霍奇金氏淋巴瘤（Hodgkin's lymphoma）、非霍奇金氏淋巴瘤、MALT淋巴瘤、套細胞淋巴瘤、邊緣區B細胞淋巴瘤、原發滲出性淋巴瘤或T細胞淋巴瘤。The method for treating a disease or condition of claim 40 , wherein the lymphoma is adult T-cell lymphoma, AIDS-related lymphoma, undifferentiated large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell lymphoma , Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin Hodgkin's lymphoma, non-Hodgkin's lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, primary exudative lymphoma, or T-cell lymphoma. 如請求項40 之用於治療疾病或病況之方法，其中該白血病係成人T細胞白血病、侵襲性NK細胞白血病、B細胞慢性淋巴球性白血病、急性單核球白血病、急性前髓細胞白血病、B細胞前淋巴球白血病、急性嗜酸性球白血病、急性紅血球白血病、急性淋巴母細胞白血病、急性巨核母細胞白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病或肥大細胞白血病。The method for treating a disease or condition of claim 40 , wherein the leukemia is adult T cell leukemia, aggressive NK cell leukemia, B cell chronic lymphocytic leukemia, acute monocytic leukemia, acute promyeloid leukemia, B Precellular lymphocytic leukemia, acute eosinophilic leukemia, acute red blood cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mast cell leukemia. 如請求項38 之方法，其中該疾病或病況係腎癌、小細胞肺癌、非小細胞肺癌、急性骨髓性白血病、多發性骨髓瘤、彌漫性大型B細胞淋巴瘤、乳癌或***癌。The method of claim 38 , wherein the disease or condition is kidney cancer, small cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, diffuse large B cell lymphoma, breast cancer or prostate cancer. 如請求項38 至 43 中任一項之方法，其進一步包含投與一或多種額外治療劑。The method of any one of claims 38 to 43 , further comprising administering one or more additional therapeutic agents. 如請求項44 之方法，其中該一或多種額外治療劑為以下中之一或多者：i）烷基化劑，其選自阿多來新（adozelesin）、六甲蜜胺（altretamine）、比折來新（bizelesin）、白消安（busulfan）、卡鉑（carboplatin）、卡波醌（carboquone）、卡莫司汀（carmustine）、苯丁酸氮芥（chlorambucil）、順鉑（cisplatin）、環磷醯胺（cyclophosphamide）、達卡巴

（dacarbazine）、雌氮芥（estramustine）、福莫司汀（fotemustine）、海普法姆（hepsulfam）、異環磷醯胺（ifosfamide）、英丙舒凡（improsulfan）、伊洛福芬（irofulven）、洛莫司汀（lomustine）、甲基二(氯乙基)胺（mechlorethamine）、美法侖（melphalan）、奧沙利鉑（oxaliplatin）、哌泊舒凡（piposulfan）、司莫司汀（semustine）、鏈脲菌素（streptozocin）、替莫唑胺（temozolomide）、噻替派（thiotepa）及曲奧舒凡（treosulfan）；ii）抗生素，其選自博萊黴素（bleomycin）、放線菌素（dactinomycin）、道諾黴素（daunorubicin）、小紅莓（doxorubicin）、表柔比星（epirubicin）、伊達比星（idarubicin）、美諾立爾（menogaril）、絲裂黴素（mitomycin）、米托蒽醌（mitoxantrone）、新卡他汀（neocarzinostatin）、噴司他汀（pentostatin）及普卡黴素（plicamycin）；iii）抗代謝物，其選自由以下組成之群：阿紮胞苷（azacitidine）、卡培他濱（capecitabine）、克拉屈濱（cladribine）、氯法拉濱（clofarabine）、阿糖胞苷（cytarabine）、地西他濱（decitabine）、氟尿苷（floxuridine）、氟達拉濱（fludarabine）、5-氟尿嘧啶（5-fluorouracil）、替加氟（ftorafur）、吉西他濱（gemcitabine）、羥基脲（hydroxyurea）、巰基嘌呤（mercaptopurine）、甲胺喋呤（methotrexate）、奈拉濱（nelarabine）、培美曲塞（pemetrexed）、雷替曲塞（raltitrexed）、硫鳥嘌呤（thioguanine）及曲美沙特（trimetrexate）；iv）免疫治療劑，其選自PD-1或PD-L1抑制劑；v）激素或激素拮抗劑，其選自由以下組成之群：恩雜魯胺（enzalutamide）、阿比特龍（abiraterone）、阿那曲唑（anastrozole）、雄激素（androgens）、布舍瑞林（buserelin）、己烯雌酚（diethylstilbestrol）、依西美坦（exemestane）、氟他胺（flutamide）、氟維司群（fulvestrant）、戈舍瑞林（goserelin）、艾多昔芬（idoxifene）、來曲唑（letrozole）、亮丙立德（leuprolide）、甲地孕酮（magestrol）、雷諾昔酚（raloxifene）、他莫昔芬（tamoxifen）及托瑞米芬（toremifene）；vi）紫杉烷（taxane），其選自DJ-927、多西他賽（docetaxel）、TPI 287、太平洋紫杉醇（paclitaxel）及DHA-太平洋紫杉醇（DHA-paclitaxel）；vii）類視黃素（retinoid），其選自亞利崔托寧（alitretinoin）、貝瑟羅汀（bexarotene）、非瑞替尼（fenretinide）、異維甲酸（isotretinoin）及維甲酸（tretinoin）；viii）生物鹼，其選自依託泊苷（etoposide）、高三尖杉酯鹼（homoharringtonine）、替尼泊苷（teniposide）、長春鹼（vinblastine）、長春新鹼（vincristine）、長春地辛（vindesine）及長春瑞賓（vinorelbine）；ix）抗血管生成劑，其選自AE-941（GW786034，Neovastat）、ABT-510、2-甲氧***（2-methoxyestradiol）、來那度胺（lenalidomide）及沙力度胺（thalidomide）；x）拓樸異構酶抑制劑，其選自安吖啶（amsacrine）、艾特咔林（edotecarin）、依昔替康（exatecan）、伊立替康（irinotecan）、SN-38(7-乙基-10-羥基-喜樹鹼)（SN-38 (7-ethyl-10-hydroxy-camptothecin)）、盧比替康（rubitecan）、拓朴替康（topotecan）及9-胺基喜樹鹼（9-aminocamptothecin）；xi）激酶抑制劑，其選自埃羅替尼（erlotinib）、吉非替尼（gefitinib）、夫拉平度（flavopiridol）、甲磺酸伊馬替尼（imatinib mesylate）、拉帕替尼（lapatinib）、索拉非尼（sorafenib）、蘋果酸舒尼替尼（sunitinib malate）、AEE-788、AG-013736、AMG 706、AMN107、BMS-354825、BMS-599626、UCN-01（7-羥基星孢菌素）（7-hydroxystaurosporine）、維羅非尼（vemurafenib）、達拉非尼（dabrafenib）、曲美替尼（trametinib）、考比替尼（cobimetinib）、司美替尼（selumetinib）及凡塔藍尼（vatalanib）；xii）靶向信號轉導抑制劑，其選自硼替佐米（bortezomib）、格爾德黴素（geldanamycin）及雷帕黴素（rapamycin）；xiii）生物反應調節劑，其選自咪喹莫特（imiquimod）、干擾素-α及介白素-2；xiv）IDO抑制劑；及xv）化學治療劑，其選自3-AP(3-胺基-2-羥基醛硫半腙)（3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone)）、阿曲生坦（altrasentan）、胺魯米特（aminoglutethimide）、阿那格雷（anagrelide）、天冬醯胺酶（asparaginase）、苔蘚蟲素-1（bryostatin-1）、西侖吉肽（cilengitide）、艾利莫耳（elesclomol）、甲磺酸艾日布林（eribulin mesylate）（E7389）、伊沙匹隆（ixabepilone）、氯尼達明（lonidamine）、馬索羅酚（masoprocol）、米托胍腙（mitoguanazone）、奧利默森（oblimersen）、舒林酸（sulindac）、睾內酯（testolactone）、噻唑呋林（tiazofurin）、mTOR抑制劑、PI3K抑制劑、Cdk4抑制劑、Akt抑制劑、Hsp90抑制劑、法呢基轉移酶抑制劑或芳香酶抑制劑（阿那曲唑來曲唑依西美坦（anastrozole letrozole exemestane））；xvi）Mek抑制劑；xvii）酪胺酸激酶抑制劑；xviii）c-Kit突變型抑制劑，xix）EGFR抑制劑、PD-1抑制劑，或xx）表觀遺傳調節劑。The method of claim 44 , wherein the one or more additional therapeutic agents are one or more of the following: i) an alkylating agent selected from the group consisting of adozelesin, altretamine, Bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, Cyclophosphamide, Dacarb

(dacarbazine), estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven , lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine ( semustine), streptozocin, temozolomide, thiotepa and treosulfan; ii) antibiotics selected from bleomycin, actinomycin ( dactinomycin), daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, rice mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from the group consisting of: azacitidine , capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine Fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine ), pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) immunotherapeutic agents selected from PD-1 or PD-L1 inhibitors ; v) hormones or hormone antagonists selected from the group consisting of: enzalutamide, abiraterone, anastrozole, androgens, Buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene , letrozole, leuprolide, magestrol, raloxifene, tamoxifen and toremifene; vi) purple Taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) retinoid, It is selected from the group consisting of alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; viii) alkaloids selected from the group consisting of etoretinoin Poside (etoposide), homoharringtonine (homoharringtonine), teniposide (teniposide), vinblastine (vinblastine), vincristine (vincristine), vindesine (vindesine) and vinorelbine (vinorelbine); ix) An anti-angiogenic agent selected from the group consisting of AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide and thalidomide ; x) a topoisomerase inhibitor selected from the group consisting of amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7- Ethyl-10-hydroxy-camptothecin) (SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan and 9-aminocamptothecin (9-aminocamptothecin); xi) kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, Lapatinib, Sorafenib b), sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine) (7- hydroxystaurosporine, vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib xii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin and rapamycin; xiii) biological response modifiers selected from imiquine imiquimod, interferon-alpha and interleukin-2; xiv) IDO inhibitors; and xv) chemotherapeutic agents selected from 3-AP (3-amino-2-hydroxyaldehyde thiosemihydrazone) (3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone)), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryozoans bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, clonidine lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyl transferase inhibitors, or aromatase inhibitors (anastrozole letrozole exemestane); xvi) Mek inhibitor; xvii) tyrosine kinase inhibitor; xviii) c-Kit mutant inhibitor, xix) EGFR inhibitor, PD-1 inhibitor, or xx) epigenetic modulator. 如請求項45 之方法，其中該一或多種額外治療劑為PD-1或PD-L1抑制劑。The method of claim 45 , wherein the one or more additional therapeutic agents are PD-1 or PD-L1 inhibitors. 如請求項46 之方法，其中該PD-1或PD-L1抑制劑為納武單抗（nivolumab）、帕博利珠單抗（pembrolizumab）、測米匹單抗（cemiplimab）、阿特珠單抗（atezolizumab）、阿維魯單抗（avelumab）或德瓦魯單抗（durvalumab）。The method of claim 46 , wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, atezolizumab (atezolizumab), avelumab (avelumab), or durvalumab (durvalumab).